Gene cluster for thienamycin biosynthesis, genetic manipulation and utility

ABSTRACT

Isolation, cloning and sequencing of the cluster of genes involved in the biosynthesis of the carbapenem thienamycin by  streptomyces cattleya,  and the use of those genes to increase thienamycin production, and/or related antibiotics, in the producing strains, and obtaining new derivatives by means of genetic manipulation which implies gene expression, mutagenesis by gene replacement and combinatorial biosynthesis.

SUMMARY OF THE INVENTION

[0001] The present invention relates to the cloning and sequencing of the thienamycin biosynthetic gene cluster from Streptomyces cattleya and the use of the genes included therein to increase yields of thienamycin, or related antibiotics, in the producer strain/s and to obtain novel derivative compounds by genetic manipulation concerning gene expression, mutagenesis by gene inactivation and combinatorial biosynthesis.

FIELD OF THE INVENTION

[0002] The present invention concerns the isolation and identification of a gene cluster involved in the biosynthesis of the carbapenem antibiotic thienamycin by Streptomyces cattleya and provides a tool for the genetic manipulation of the cluster in order to increase thienamycin production and to obtain novel derivatives with improved properties.

BACKGROUND OF THE INVENTION

[0003] Thienamycin (FIG. 1) is the first β-lactam antibiotic of the carbapenem family that was isolated (Kahan et al., J. Antibiot. v. 23: 1255-1265, 1979). It is one of the most potent and broadest in activity spectrum of all known antibiotics and it has an important clinical use in the treatment of infectious diseases, particularly in hospitals. Thienamycin is active against Gram-positive and Gram-negative pathogenic bacteria, both aerobic and anaerobic (including clinical isolates resistant to classic β-lactam antibiotics) and it is highly resistant to bacterial β-lactamases. It is produced at low level by the wild type strain Streptomyces cattleya NRRL 8057, that also produces the convenctional β-lactam antibiotic cephamycin C. Thienamycin is highly unstable and a most stable derivative, named imipenem (N-formidoil thienamycin), is the antibiotic of choice for clinical usage.

[0004] The development of recombinant DNA technology has provided a powerful tool that has contributed to the knowledge of gene clusters involved in antibiotic biosynthesis in many actinomycete species. This technology can now be applied to increase yields of antibiotics in the producer strains and to obtain novel derivative compounds with improved properties by expression of genes from selected biosynthetic pathways through combinatorial biosynthesis. Recombinant DNA technology has made possible the isolation of complete antibiotic biosynthetic gene clusters, using among other screening strategies, the screening of gene libraries with DNA probes. This approach relies on the existence of previous genetic information concerning the pathway or related pathways that could allow the construction of a probe using information from a partial aminoacid sequence of a biosynthetic enzyme.

[0005] Biosynthesis of classic β-lactam antibiotics, as penicillins, cephalosporins and cephamycins is a well known process that takes place by condensation of L-α-aminoadipic acid, L-cysteine and L-valine to form the tripeptide δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV) by a non-ribosomal peptide synthetase, named ACVS (encoded by the pcbAB gene). Cyclization of this tripeptide is then carried out by isopenicillin N synthase o IPNS (encoded by the pcbC gene). These two steps are common in all producers of convectional β-lactam antibiotics, both bacteria and fungi, and the corresponding genes and enzymes are very well known and are conserved among all producers despite their phylogenetic origin.

[0006] On the other hand, there is biochemical evidence supporting that thienamycin biosynthesis in Streptomyces cattleya could proceed through an alternative pathway to the classic β-lactam antibiotic cephamycin C, also produced by this strain (Williamson et al., J. Biol. Chem. v. 260: 4637-4647, 1985). The bicyclic ring in thienamycin derives from acetate β-lactam carbons) and glutamate (pyrrolidine ring) and it has been proposed that it is formed after condensation of acetyl-S-CoA with y-glutamylphosphate instead of the ACV tripeptide formation as occurs in penicillins, cephalosporins and cephamycins biosynthesis (Williamson et al., 1985, supra). From the genetic point of view, there are no previous reports in the literature concerning the sequencing of the thienamycin biosynthetic gene cluster or any other carbapenem antibiotic produced by Streptomyces species.

[0007] A novel mechanism for the biosynthesis of the β-lactam ring, has been reported lately for the biosynthesis of the non classic β-lactams, carbapenems and clavams. These two groups of β-lactam compounds are synthesized by a mechanism never reported in classic β-lactam antibiotic biosynthesis. This alternative mechanism for β-lactam ring biosynthesis involves a novel biosynthetic enzyme, a β-lactam synthetase, that was found to participate first in the biosynthesis of the carbapenem antibiotic (1-carbapen-2-em-3-carboxylic acid) produced by the Gram-negative bacterium Erwinia carotovora (now Pectobacterium carotovorum), from where the gene cluster was cloned (McGowan et al., Mol Microbiol v. 22: 415-426, 1996; Salmond et al. U.S. Pat. No. US0,058,719,22A, 1999). The same mechanism, involving a β-lactam synthetase, was found to be involved in the biosynthesis of the clavam clavulanic acid and forms part of the gene cluster for this β-lactamase inhibitor in the Gram-positive bacterium Streptomyces clavuligerus (Bachmann et al., Proc Nati Acad Sci USA v. 95: 9082-9086, 1998).

[0008] The present invention is directed to the aim of the cloning and sequencing of the thienamycin biosynthetic gene cluster from the producing strain Streptomyces cattleya NRRL 8057. The genetic information available about the biosynthetic enzyme, β-lactam synthetase, has been used to design synthetic oligonucleotides and generate a probe that allowed the cloning of the thienamycin gene cluster from Streptomyces cattleya. This is the first instance wherein the gene cluster for producing thienamycin has been isolated. The invention provides as well a tool for the genetic manipulation of the cluster in order to increase thienamycin production and to obtain novel potential derivatives with improved properties.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009]FIG. 1. Structure of the carbapenem antibiotic thienamycin.

[0010]FIG. 2. Diagram showing a schematic representation of the restriction endonuclease map of the gene cluster for thienamycin biosynthesis of Streptomyces cattleya NRRL 8057.

[0011]FIG. 3. Schematic representation of inserts included in cosmid cosCAT25 and in plasmids pLE14 and pLE22.

[0012]FIG. 4. Insertional inactivation of ORF6 by gene replacement.

[0013] (A) Construction of the plasmids pHZLE6R and pHZLE6F to be used in the gene inactivation.

[0014] (B) Gene replacement of the Streptomyces cattleya wild type strain by insertion of an apramycin resistance cassette in ORF6.

[0015]FIG. 5. HPLC analysis:

[0016] (A) Thienamycin production in the wild type strain of Streptomyces cattleya, with indication of the thienamycin absorption spectrum.

[0017] (B) Thienamycin non producing mutant obtained after inactivation of ORF6 by gene replacement using pHZLE6F.

[0018] (C) Thienamycin non producing mutant obtained after inactivation of ORF6 by gene replacement using pHZLE6R.

DETAILED DESCRIPTION OF THE INVENTION

[0019] This invention relates to the cloning and sequencing of the gene cluster encoding a β-lactam synthetase involved in the biosynthesis of the carbapenem antibiotic thienamycin. The invention thus relates to novel genes and nucleic acid molecules encoding proteins/polypeptides exhibiting functional activities involved in thienamycin biosynthesis, such proteins/polypeptides themselves, and their uses both in increasing thienamycin production in Streptomyces cattleya and in the generation of novel thienamycin derivatives.

[0020] The experimental procedures of the present invention include molecular biology methods conventional in the art. Detailed description of the techniques not explained here are given in the manuals by Hopwood et al. “Genetic manipulation of Streptomyces: a laboratory manual”. The John Innes Foundation, Norwich (1985); by Sambrook et al. “Molecular cloning: a laboratory manual” (1989) and by Kieser et al. “Practical Streptomyces genetics”. The John Innes Foundation, Norwich (2000).

[0021] In order to clone the thienamycin biosynthetic gene cluster, a chromosomal DNA cosmid library from Streptomyces cattleya NRRL 8057 was constructed in Escherichia coli, using the bifunctional cosmid pKC505.

[0022] For the isolation of the thienamycin biosynthetic gene cluster we have used information concerning a novel biosynthetic enzyme, β-lactam synthetase, above mentioned, to obtain a genetic probe. The strategy was based in the design of a pair of degenerated oligonucleotides according to the conserved regions between the two available β-lactam synthetase sequences (Bachmann et al., 1998, supra and McGowan et al., 1996, supra) as were deduced from the protein alignment. The synthetic oligonucleotides were BLS1 (5′ ATCGTCTAGACSGASACSTCSAACGAGTTS-3′) and BLS4 (5′-ATCGMGCTTSGASCCCTCGTGGACGCC-3′) and were used in PCR-assisted amplification to obtain a probe from the S. cattleya chromosome.

[0023] Three cosmid clones, called cosCAT25, cosCAT22 and cosCAT14, were isolated by hibridization with the amplified probe. One cosmid, cosCAT25 (FIG. 2 and 3), was presumed to contain most of the thienamycin gene cluster and was selected for sequencing. In addition two overlapping clones, pLE22 and pLE14, (obtained by subcloning adjacent BamHI fragments from the cosCAT22 and cosCAT14) were further sequenced. Analysis of the nucleotide sequence revealed the presence of 28 complete open reading frames (ORFs) and two incomplete ORFs (FIG. 2 and 3), most of them probably involved in thienamycin biosynthesis. The functions of the genes were concluded after comparison of the deduced amino acid sequences with known sequences available in the data bases and will be described herein below. Some of them would encode structural biosynthetic enzymes, transcriptional activators, proteins involved in exportation, quorum sensing, etc. Among the ORFs coding for structural functions it has been found ORF5, whose deduced product is highly homologous to the β-lactam synthetase proteins that were used in the design of the probe (Bachmann et al., 1998, supra and MacGowan et al., 1996, supra). Two ORFs, (ORF2 and ORF12) would encode regulatory proteins, in fact transcriptional activators highly homologous to ClaR and CcaR from Streptomyces clavuligerus. ClaR works as a transcriptional activator of clavulanic acid biosynthetic genes (Pérez LLarena et al., J. Bacteriol. v. 179: 2053-2059, 1997; U.S. Pat. No. US0,058,210,77A, 1998) and CcaR activates transcription of both clavulanic acid and cephamycin C biosynthetic genes (Paradkar et al., J. Bacteriol. v. 178:6266-6274, 1998).

[0024] The involvement of this gene cluster in thienamycin biosynthesis has been demostrated by insertional inactivation of one of the ORFs in the middle of the cluster (ORF6 which forms part of the same transcriptional unit than the β-lactam synthetase homologue), through the insertion of an apramycin resistance cassette generating a thienamycin non producing mutant, as was determined by bioassay and HPLC analysis. The strategy followed for this process has been a gene replacement experiment in which the introduction of plasmid DNA into Streptomyces cattleya was achieved by using intergeneric conjugation from Escherichia coli, according to the method from Mazodier et al., J. Bacteriol. v. 171: 3583-3585 (1989).

[0025] The present invention includes a method for increasing the thienamycin producing ability of Streptomyces cattleya. It consists in the overexpression of either (1) regulatory genes from the thienamycin gene cluster, capable of activating gene expression of the cluster, or (2) structural biosynthetic genes, preferably coding for a product that is rate-limiting in the biosynthetic pathway.

[0026] The invention further comprises several procedures for manipulating the biosynthetic genes in order to obtain novel thienamycin derivatives: (1) by gene replacement techniques generating mutants in the late steps in thienamycin biosynthesis which could lead to the accumulation of thienamycin intermediates, and (2) by expression of different set of genes in heterologous hosts (β-lactam producers or non producers) in combinatorial biosynthesis experiments.

[0027] The present invention will be described in more detailed and illustrated herein below through the following non limiting examples.

EXAMPLE 1

[0028] Cloning of the Gene Cluster for Thienamycin Biosynthesis

[0029] 1.1. Bacterial Strains, Plasmids and Growth Conditions

[0030] Bacterial strains and plasmids used in this study are listed in Table 1. S. cattleya NRRL 8057 was cultured for sporulation on solid Bennet medium (Locci et al. J. of Microbiol., v. 17: 1-60, 1969); for antibiotic production was cultured in liquid R5A medium (Fernández et al, J Bacteriol, v. 180: 4929-4937, 1998) using an inoculum previously grown in liquid TSB medium (Merck). Intergeneric conjugation from E. coli ET12567 (pUB307) into S. cattleya was done according to Mazodier et al. (1989), supra and Flett et al., FEMS Microbial Lett., v. 155: 223-229 (1997). E. coli strains were grown and transformed as described in Sambrook et al. (1989), supra. TABLE 1 Bacterial strains and Plasmids used in this study Strain, plasmid Properties Source or reference E. coli DH10B general cloning host Gibco E. coil ED8767 host for the cosmid Sambrook et al. 1987, gene library supra E. coil ET12567 strain for intergeneric MacNeil et al, Gene, conjugation v. 111:61-68, 1992 S. aureus thienamycin sensitive ATCC ATCC 6538P S. cattleya wild type, thienamycin Kahan et al, 1979, NRRL 8057 producer supra pBluescript SK E.coli cloning vector Stratagene pKC505 cosmid for gene Richardson et al., Gene, library construction v. 61:231-241, 1987 pUG18 E. coil cloning vector Pharmacia pHZ1358 cosmid for intergeneric Sun et al., Microbiology, conjugation v.148:361-371, 2002 pUB307 plasmid for Bennet et al., MGG, intergeneric v. 54:205-211, 1977 conjugation

[0031] 1.2. Analysis of Thienamycin Production

[0032] Thienamycin production was qualitatively assayed by bioassay against the thienamycin sensitive strain Staphylococcus aureus ATCC 6538P (cephamycin C resistant). Thienamycin identification and quantitative analysis was performed by HPLC using a reversed phase column (Symmetry C18, 4.6×250 mm; Waters) with acetonitrile and 0.1% trifluoroacetic acid in water as the mobile phase (5:95), at a flow rate of 1 ml/min. Detection and spectral characterization of peaks were made with a photodiode array detector and Millennium software (Waters), and quantification was done after signal integration at 311 nm.

[0033] 1.3. DNA Manipulation

[0034] Plasmid, and total DNA preparations, endonuclease digestions, ligations, etc. were performed as described previously (Sambrook et al., 1989, supra; Kieser et al., 2000, supra; Hopwood et al., 1985, supra). DNA fragments were isolated from agarose gels using the QUIAquick Gel Extraction Kit from QIAGEN (Hilden, Germany) labelled with the use of the DIG DNA Labelling and Detection Kit from Roche Diagnostics (Manheim, Germany) and used for Southern blot analysis according to the manufacturer's manual. DNA sequencing was performed at QIAGEN GmbH (Germany), and the data were analysed with the GCG software (Devereux et al., Nucleic Acids Res. v. 12: 387-395, 1984).

[0035] 1.4. PCR-Assisted Amplification and Cloning of a DNA Fragment Encoding Part of a β-Lactam Synthetase from the S. Cattleya NRRL8057 Genome

[0036] The strategy developed for the cloning of the thienamycin gene cluster was the genetic homology with previously known clusters corresponding to pathways for β-lactam biosynthesis. Available genetic information concerning a β-lactam synthetase, a novel biochemical mechanism for β-lactam biosynthesis, was used for this purpose. Thus, in order to obtain the DNA encoding the thienamycin biosynthesis genes, a S. cattleya NRRL 8057 cosmid gene library was probed with labelled β-lactam synthetase-encoding DNA.

[0037] To construct the DNA probe for the screening, degenerate oligonucleotide primers were designed according to conserved amino acid regions within known β-lactam synthetases, β-Is from S. clavuligerus (Bachmann et al., 1998, supra) and carA from E. carotovora (McGowan et al., 1996, supra). The degenerate primers used for amplification corresponded to the conserved regions between the two available β-lactam synthetase sequences, as deduced from the protein alignment, and were designed according to the codon usage table for Streptomyces (Wright & Bibb, Gene, v. 113: 55-56, 1992). The selection of the regions for oligonucleotide design was done avoiding the conserved regions with the related proteins as asparragine synthetase. The synthetic sense nucleotide primer, BLS1, corresponded to the amino acid sequence Thr Asp (Glu) Thr (Leu) Ser Asn Glu Phe and had the sequence 5′- ATCGTCTAG ACG/C GAG/C ACG/C TCG/C AAC GAG TTG/C-3′ (SEQ ID NO: 32), including an Xbal restriction site for cloning (underlined). The antisense nucleotide primer, BLS4, corresponded to the amino acid sequence Gly Val (IIe) His Glu Gly Ser and had the sequence 5′-ATCGAAGCTT G/CGA G/CCC CTC GTG GAC GCC-3′) (SEQ ID NO: 33), including an HindIII restriction site for cloning (underlined). Total DNA obtained from S. cattleya NRRL 8057 cultured on TSB medium (Tryptone Soya Broth, Oxoid) was isolated as described (Kieser et al., 2000, supra). The total genomic DNA from S. cattleya NRRL 8057 was further used as a template for polymerase chain reaction (PCR)-assisted amplification of the DNA fragment from the genome of this organism with the use of BLS1 and BLS4 oligonucleotide primers. It was assumed that both oligonucleotides would allow the amplification of an internal fragment of the β-lactam synthetase encoding gene and that the resulting PCR product would be of approx 0.5 kb in size. The PCR reaction was carried out in a total volume of 50 μl and the PCR mixture contained 0.1 μg of S. cattleya NRRL 8057 total DNA, 200 pm of each oligonucleotide primer, dNTPs (final concentration of 200 μM), 1×PCR buffer from Taq DNA polymerase and 5U of Taq DNA polymerase (Gibco BRL). The PCR was performed on the MJ Research MiniCycler™ with the following program: 1 cycle of denaturation at 98° C. (5 min), 30 cycles of denaturation/annealing/synthesis at 94° C. (1 min)/65° C. (1min)/72° C. (1 min) and 1 cycle of final extension at 72° C. (5 min). A DNA fragment obtained with this procedure was cloned in the Escherichia coli vector pUC18 (using the Xbal/HindIII restriction sites included in the synthetic oligonucleotides) and was subjected to further DNA sequencing using standard techniques in Molecular Biology. DNA sequence analysis of the resulting amplified fragment followed by conceptual translation and database search revealed that the PCR product encoded a region homologous to part of known β-lactam synthetases (Bachmann et al., 1998, supra and McGowan et al., 1996, supra). However, the amplified DNA fragment was shorter than expected initially. In fact it was of 0.22 kb in size, due to the annealing of the BLS1 oligonucleotide to an internal region of the expected in the initial design. Once confirmed that the amplified DNA fragment encodes part of a β-lactam synthetase it was used as a probe for screening a S. cattleya NRRL 8057 cosmid gene library (see below).

[0038] 1.5. Construction and Screening of the S. Cattleya NRRL8057 Gene Library

[0039] The S. cattleya NRRL 8057 gene library was constructed in the bifunctional cosmid pKC505 (Richardson et al., Gene, v. 61: 231-241, 1987), which is able of replication both in Escherichia coli and Streptomyces. Total DNA from S. cattleya NRRL 8057, isolated as described above, was partially digested with Sau3Al and fragments of about 35 kb were dephosphorylated by alkaline phosphatase treatment (Roche Diagnostics, Mannheim). The cosmid vector was linearized with Hpal, dephosphorylated, and digested with BamHI to generate both cosmid arms. Insert DNAs and vector were ligated and packaged in vitro using a commercial packaging kit from Roche Diagnostics Mannheim. The recombinant phage particles were used to infect E. coli ED8767 and transductants selected on trypticasein-soy agar (TSA) plates (containing 10 μgml⁻¹ tobramycin). Approximately. 3000 transductants were cultured on microtiter plates and, after incubation at 28° C. for 24 h, kept with 25% glycerol at −70° C.

[0040] In order to clone the gene cluster for thienamycin biosynthesis the genomic library of S. cattleya NRRL 8057 was screened by in situ colony hybridization with the amplified probe corresponding to an internal fragment of the β-lactam synthetase encoding gene (see above). For the screening of the cosmid library the DNA probe was labelled with α-P³² dCTP and hybridization was carried out using the Rediprime DNA labelling system (Amersham) according to the manufacturer's manual. Three hybridising cosmid clones, cosCAT25, cosCAT22 and cosCAT14, were isolated and selected for further analysis. After Southern blot analysis using the same probe it was determined that the three cosmids show overlapping restriction maps and one of them, cosCAT25 (FIG. 2 and 3), was selected for sequencing analysis. In addition, two overlapping clones, pLE22 and pLE14 (FIG. 2 and 3), obtained after subcloning adjacent BamHI fragments from the cosCAT22 and cosCAT14, were also sequenced.

EXAMPLE 2

[0041] Sequence Analysis of the Gene Cluster for Thienamycin Biosynthesis and the Deduced Functions from the Genes

[0042] Sequence analyses were made using the GCG sequence analysis software package (Version 8: Genetics Computer Group, Madison, Wis., USA). The translation table was modified to accept also GTG as a start codon. Codon usage was analyzed using published data (Wright and Bibb, 1992, supra)

[0043] Computer-assisted analysis of the DNA sequence (FIG. 2) comprised the region cloned in cosmid cosCAT25 (26571 bp) and the two overlapping BamHI fragments from cosmids cosCAT22 and cosCAT14 that were cloned in pLE14 (4806 bp) and pLE22 (6144 bp) (FIG. 3). According to the CODONPREFERENCE program the sequenced DNA fragment revealed 28 complete open reading frames (ORFs) and two 5′ ends of the other ORFs (ORFX and ORFW5). The functions of the genes were concluded by comparing the amino acid sequences translated from their base sequences to the known sequences in the data banks. The results are shown in Table 2 referring to the sequence data given in the application. TABLE 2 A- mino Gene Position acids Deduced function Remarks orfX  −751 >250 unknown not complete compl SegID.NO:2 orfX1  1034-1924 296 unknown SegID.NO:3 orfZ  1940-2719 259 putative SeqID.NO:4 compl oxidoreductase orfZ1  2850-3932 360 putative SeqIDNO:5 compl efflux pump regulador orfZ2  4117-4755 212 putative SeqID.NO:6 efflux protein LysE family orfZ3  4945-6036 363 putative SegID.NO:7 oxidoreductase orf1  6288-7172 294 enoyl-CoA SeqID.NO:8 hydratase CarB homologue orf1b  7156-8139 327 unknown SeqID.NO:9 compl orf1c  8136-8927 263 putative SeqID.NO:10 compl hydroxylase orfA  9171-9845 224 putative epoxide SeqID.NO:11 hydrolase orf2  9767-11197 476 putative transcriptional SeqlD.NO:12 compl activator ClaR homologue orf2c 11289-12740 483 putative transport SeqID.NO:13 compl protein orf3 12737-14782 681 putative SeqID.NO:14 compl methyltransferase orf4 14838-16262 474 putative SeqID.NO:15 compl methyltransferase orf5 16234-17610 458 putative β-lactam SeqID.NO:16 compl synthetase orf6 17612-18715 367 unknown SeqID.NO:17 compl. orf7 18754-20172 472 unknown SeqID.NO:18 compl orf8 20169-21623 484 putative SeqID.NO:19 compl methyltransferase orf8d 22038-22817 259 unknown SeqID.NO:20 orf9 22912-23634 240 unknown SeqID.NO:21 compl orf10 23744-24733 329 unknown SeqID.NO:22 orf11 24784-25983 399 unknown SeqID.NO:23 orf12 26146-26952 268 transcriptional SeqID.NO:24 activator CcaR homologue orf13 26980-27393 137 unknown SeqID.NO:25 compl orfY 27614-28156 180 unknown SeqID.NO:26 compl orfW1 28224-28412 62 unknown SeqID.NO:27 orfW2 28485-29246 253 unknown SeqID.NO:28 orfW3 29382-29567 61 unknown SeqID.NO:29 orfW4 29766-30197 143 unknown SeqID.NO:30 orfW5 30695- >545 unknown not complete SeqID.NO:31

EXAMPLE 3

[0044] Insertional Inactivation of the Thienamycin Gene Cluster by Gene Replacement

[0045] In order to demonstrate the involvement of the cloned gene cluster in thienamycin biosynthesis, ORF6, immediately upstream of the β-lactam synthetase homologue (ORF5) was inactivated by insertion of an apramycin resistance cassette containing the aac(3)IV gene (Stanzak et al. Biotechnology v. 4: 229-232, 1986). For insertional inactivation of chromosomal genes in Streptomyces the gene inactivation is usually created on a suitable vector in E. coli before introducing the construct into Streptomyces for recombination with the chromosome. For this purpose, a 8.4 kb DNA BamHI fragment from cosmid cosCAT25 was first cloned into the pUC18 vector in E. coli, resulting in the plasmid pLESC6 (FIG. 4A). In this later construction, an apramycin resistance cassette was independently inserted in both orientations in the unique Bg/II restriction site (blunt ended) localized in the ORF6 coding region, generating pLE6F (with the apramycin cassette in forward orientation) and pLE6R (with the apramycin cassette in reverse orientation). From these two constructions in which ORF6 was insertional inactivated by the apramycin resistance cassette, the 9.9 kb DNA BamHI fragment was excised and ligated to the conjugative vector pHZ1358, previously digested with the same restriction enzyme, generating pHZLE6F and pHLE6R (FIG. 4A).

[0046] The recombinant plasmids constructed for the gene replacement experiments (pHZLE6F and pHZLE6C) were introduced into S. cattleya by intergenic conjugation from E. coli ET12567 (pUB307) as described by Mazodier et al. (1989), supra. A double crossover is necessary to obtain the replacement of the wild type copy of the gene by the mutated one. The transconjugants in which a double crossover event has happened were selected for apramycin resistance and thiostrepton sensitivity. Replacement in the chromosome of the wild type copy of the gene by the mutated one was confirmed in the transconjugants by Southern blot analysis with the use of labelled 8.4 kb BamHI fragment from plasmid pLESC6 (FIG. 4B). One of each replaced mutant (with apramycin gene inserted in different orientation) was tested for thienamycin production in parallel with the parental strain NRRL 8057 by bioassay and HPLC (see above for methods under “analysis of thienamycin production”). Both mutants, with independence of the apramycin gene orientation, were shown to be non producers of thienamycin (FIG. 5), confirming the involvement of the cluster in thienamycin biosynthesis.

[0047] Deposited Microorganisms Microorganism Accession number Date of deposit E. coli ED8767/cosCAT25 CECT 5877 March 7^(th) 2002 E. coli DH10B/pLE14 CECT 5876 March 7^(th) 2002 E. coli DH10B/pLE22 CECT 5875 March 7^(th) 2002

[0048]

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 33 <210> SEQ ID NO 1 <211> LENGTH: 32329 <212> TYPE: DNA <213> ORGANISM: Streptomyces cattleya <300> PUBLICATION INFORMATION: <301> AUTHORS: Nunez, Luz Elena Mendez, Carmen Brana, Alfredo F. Blanco, Gloria Salas, Jose A. <302> TITLE: The Biosynthetic Gene Cluster for the ??Lactam Carbapenem Thienamycin in Streptomyces cattleya <303> JOURNAL: Chemistry and Biology <304> VOLUME: 10 <306> PAGES: 301-311 <307> DATE: 2003-04-21 <308> DATABASE ACCESSION NUMBER: AJ421798 <309> DATABASE ENTRY DATE: 2001-12-11 <400> SEQUENCE: 1 ggatccgcgc ggcggcccgg gcgggcacct cggtgcgcca ggcacgggcg atctccggcc 60 gcgcgagcac cgccttgagc agggcgtaca gcggtgagcg cggcggggcg gcgcgcaggt 120 cgtcggagat ctcgcacagc agcggcacca gccacccctc gtaccagtcg gccagcagcc 180 gcggggcgtc ggggtggagg cagatgaatc gggccaggtt ctcccggggt atggcctcgg 240 gcacccgggc gacgccggag aagagccggg tgtaggcggc gttgcaggcc agcagccgcc 300 aggcggggtc gcgcaggtag gcgggcatcc cgacgtcccg gaagccgcgg tgccattcgc 360 gggcgaagcc ggccgggtcg ccggggtgcg gggtctcggg ggcgggggcc gggcgggcgg 420 cgggggtacg ggaaccggcc agcccggcca gttcccgctc ctcctcgcgg gtgagggcga 480 gggcggcggc gaggtcggcg acgcggcgcg ggtccacgcc gtgctgtccg cgttcccagt 540 tgctgaccgt gcgtgtgctg acgtccagcc gccaggccag cccttcctgg ctgagtcctg 600 agcgcagtcg gcgggcgcgc aggaacgccg ggagcgggtg gccggccgac ggcccgccgg 660 gcggggcggc gcggtcgggg cggcggtcgg ccggccggtg ccgcgctccg ccgccgcggt 720 cgccgagggc ggggaacgaa cgtggaatca tgtgcggtac gccttgtcga agccgatcgg 780 acggtgacgg gtcacggacg gtcacggagg aggtggccgg ggcgcgacct ggcgccggcc 840 cccgtcacgg acgtggcgcc gtgctgtcgc cgccgtcggt gaccaggccg gactcccccg 900 gctcgacctg gtacgggcac cgattgtggc cgttgtggcg ggggttgggg agagaagcga 960 tttccacgga cgtccgatcc ctattattca cctttcacca accggcccgc cggtttctgt 1020 tctggatgga gacatgaccg acgcgcaacc ttccggcccc gtcgtggagc acggacgcgg 1080 agacctcacc gccgaggagc ggcgccagaa gctgtccttc ctgcgcgaga agcgcgacag 1140 cgtcgaccgg tcctccttcg aggcccgcta ccccgtcgag gtgccacggc ggctccccgg 1200 ccggggccgc cacgcccccg ggctcaccct ggtcgagatg ggccgcctgc tcggcctgcg 1260 ggacggctcg tggtacgcgg acctggagcg cggccaggtg gacaacgccc cggtggaccg 1320 gctgttcaag gtcgccgagc tactggacct gacgcctcgt cagtacgagt tcctgtgcgt 1380 gtacgcctgc cggcccaagc ccggttaccc ggcggccggg ctccccggcg gctaccggga 1440 ggtgctcgac ctgtaccagg ggccggcgta cttccaggac gccgggtgga acctgctcag 1500 gccgaagatg tacaacgcgg cggccgaagc gctcttcaac ggcatccccg acgacttcaa 1560 cttcatccgc tgggtgctgc tggaacggtc ggtgcgccgg ccccccgagg gcggccggcg 1620 ccacgcctgg ctgccggact tctggcaggt gtgggcgccg cgcgcgctgc cggtggtacg 1680 ggccgcgtac gtcgcccggc cggacaacgc caccctcgcc cggctccacg ccgacctggc 1740 ggccgacccc gagatcggcc ccatctacca gggccgtctg ccgccctacc cgcacaccga 1800 cggcgacctg cgtccgttcg tccacggcag caccggggaa cgcggcatgg tgcggatcaa 1860 cgtcctcacc ccgcgcggca gcgacgacac cctgatgctg ctcaactggc accccggcgc 1920 ctgacaccgg gcacatccct cagacggtct tgagcgcgcc gccgtcgatc acgtagtcgg 1980 cgccgtggac gctggccgcc aggtcggacc cgaggaaggc gatcaggtcg gccacctcgc 2040 ccggttcgac cagccggccg gtcaactggc cggagcgggc gggcactcgg gccacgtagt 2100 cggccagctc ctggccgccg agggcggcct gctgggcgcc gtagccgtcc gggtcctccc 2160 acaccggggt gcgggtgggc cccggcgaga cggtgttgac ccggaccccg cgcggcccga 2220 actcggcggc gagcgccttg cccagggtgt tgagcgcggc cttggcggtg gcgtagtcga 2280 tcggcccggt ggcgttgcgg gcgccgatcg aggagacgtt gacgatcgcg ccgcgccgct 2340 cgatcaggga gggcagggcg gcccggatca ggcgtaccgg ggcgaagaag ttgagcgccc 2400 aggagcgttc ccagatctcg tcgtcggcgg tgaggaaccc ggccgccgtg aagtggtcgc 2460 cgccaccggc gttgttgacc agcaggtcga tcccgcccag ttcggccagg gcacgctgga 2520 ccagctccgc gcagccctcg ggggtgctga ggtcgaccgc caccggaacc gcgccggcgt 2580 ccttcaactc cgcggtgacg gtccgcgcgg cgcccaccac ccggaccccc tcgccggtca 2640 gcgtccgtac caccgccagc ccgatccccc ggctcgcacc ggtcaccaca gcggtcttcc 2700 ccgacatccg caggtccatc gtgtcctctc ggtagcaact gctcccgcca cgctatacgc 2760 acccgggccg cgtcccggtc ggcgcgcggt ggccggtaac cgccgttcat gcaagggggt 2820 ttcatgatgc cgcccggacg cgacgtgcct cagccgcgcc ggggcgtggc ggccaccgcc 2880 cgggcggcgc cggggccttg ggcccgggcg gtgacgcggg cggaggccag gcggatcgcg 2940 gtttcggtgc ggtcgtcgac ggcggggacg ccggccgcgg cggcgaaggc gccggagggg 3000 tcgtggacca cgcggagcgg gggccgggcc gacgctggga aggcctggcg caggcagccg 3060 cagagttcgg cgacggacag ccgggcgagg gcgccgagtt cgccggggtc ggcggtgacg 3120 agtacggcgg tgaccggggt gtccggcggc gcggcgcgta ccgcatcctc ggcggcctcc 3180 agccggtgca gtccgaggac ggtgaccacc tggtccggtt cgccgtccgc cgggaggggg 3240 tcgccggtga ccgcgtcggt cgcgggcggc ggggaccacg gttcgtcgac gtggtggacg 3300 ggcggcaggc cgggcgcggg cggcgggtcg tcgtccagtg gcaggccggc caggcgctcg 3360 cagacccgta cggcgtcgag cgggtcgagg aaaccgggcg cggcggcggc cagttgggcg 3420 gtgccgtgca gtgcggtgag gacggcctcg gcgacgcgga ccatgcggcg ggcggggcgt 3480 ccggcgggct ccagccgttc cagcgcgagg ccgagcagga tcgcgtcgag cttcagcagc 3540 tgggcgaagg gccggcgggt ggcggcgtcg gtgatcacct cgggcatcag gtccatggcg 3600 agccgggccg ggccggggcc gtcgtccccg gcgggcggca gccgcgagac ccaggcccgg 3660 gcgaacgcgg ccagggcgtc gccgccggag cgcaccggtc gcggcggtgg tccctccggc 3720 acgcgttcgg caagcgcggc cagcacggcg aagtagagcg cccgcttgcc ggggaagttg 3780 gagtagaccg caccacgggt gagcccggcg cgctcggcga tggcgtcgat cctggcgtcc 3840 cggtagccgc gttcggcgaa ctcctcgcgg gcggcgtcca acaccttgtc gcggttgcgt 3900 tcctgggtct ccgccctggt cagccgggcc atcgtcctcc tcgccacggg gccgggcacg 3960 gtcggccacg gccggttcgc cggtgacggc cggcgccggg aaagcgcttg ccacgcgccc 4020 ctggtcacca tatcgccgcg ttccccgcgc acgcggggcg gccgggggcg cgggtggcgg 4080 caatcccgtg gacaccgtgc gctcgcgcgc cccacgatgg agcccatgct caccaccgca 4140 ctcgcgttcc tcggcgcctg cgtgctgatc gccgccgcgc ccggtcccag cacgatgctc 4200 atcatccgcc agtcgctgca cagcagacgg gccggtttcc tgaccgttct gggcaacgag 4260 accggggtgc tcacctgggg cgtggtggcg gcgctcgggc tgaccgcgct gctggccgcc 4320 tcccgcacgg cgtacgacgt gatgcggatc ggcggggcgg tggtgctggt gtggtacggc 4380 gtgcagacgc tgcgggccgc gcggcgcggc gaggcacggc cctccgccgc cgacgacgag 4440 gcggcggtgg tgccccgttc cggctggaag atctaccggt ccgggctgct gctcaacctc 4500 gccaacccca aggcggccgt cttcgccatg tccttcctgc cgcagttcgt cccggccggt 4560 gcgcccaagc tgccggtgat caccgcgctc gccgcgttcc aggcgctctt cgaggtcggg 4620 tactacggga tgtacgtgtg gttcgtcggc cggatgaaga gggtgatctc ccgggcgggc 4680 gtgcggcgcc ggctggagca ggtgtcgggg ggcgtgctgg tgctgctggg catccggatg 4740 gcggtcgaga gctgacgtag cgtcagctac ccggtaggcc cggcgcgtgc ggcgcgtcac 4800 ggatccgtgc ggcgccgccc ggcccggcgt tcgcccccgc cgccgccccg aacaccacca 4860 caccaccgga cccgtaccgc tgaccgggta ccggcggcgg gcataccggg acgggggacg 4920 agggctaccg aggcgggtga cggcgtgacg cttcccaccg agacctgggc ggtgcggatc 4980 caccggcacg gcgggccgga ggtgctcgtc cacgaacggc tgccgttgcc gccgctcggc 5040 ccggccgacg tcctggtcgc cgtcgacacc gcctcggtct ccggctggga cgtgaagtac 5100 cggcgcggac tgccgccggg tgcgcggctg cccggccggg aacggtaccg gctgccgctg 5160 caactcggcc gcgaggcggc ggggacggtg ctcgccaccg ggccggaggc ggccggccgc 5220 ttccgccccg gagaccgggt ggtcgccgtc gtccacccgg agaacccgcg cgccccggag 5280 accgtacgcg gcctgggaaa cctctccacc ggcatcgccc tccccggcca ccaggcgccg 5340 ggcggctacg cacgctacct gatctgccat caggacatgt ggctgccctt gccgtccggc 5400 gtcgacctcg aacaggccgc cgtgacgctg tggccgtacg cgacctgcca ccgcgtactg 5460 cgcgaccggt tgcgggtggc gctcggcgag acgctgctgg tgtgcggcgc caccggggcg 5520 atggggctgg cggcgctgcg actggcccgg ctgaccgggg tgcgggtgat cgcgatgacc 5580 cgctaccggg ccaaggagcg ggcgttgcgg acggccggcg cggacgaggt ggtggtcgcc 5640 ggtgatccgc ggcaggcgtg cgaggcggtg cgcgcgctca ccggcgggga aggcgtggac 5700 cacgcggtgg acttcaccgg cagcgccgcg ctgctgcggc tggccgtcga ctcgctgcgc 5760 ctcggcggcc ggctgtgccc ggccgccacc cagcgtccgc ccggcccgct cccggtgacc 5820 accggtgacc tcacccggct ggagatcacc gtgtacggca tccgcggcgc ccgccaccgg 5880 gacgcgctgc gggtgctcgc cctgctgggc gacggcagcc tgccggccac cccgatcgcc 5940 gcccgcttcc cgctgtcccg ggccggcgcc gcccacgagt tcctggaaca caacaccacg 6000 gctgtcggcc gcgtggtgct caaacccggc tggtgaccga cgcgacccgc cgccggccgc 6060 cccgggcggc gtaccggccc gccggattcc gggcgggacc tcgggcgtcg gccgggaata 6120 tgcgcgtgat cagcgttgac tgccctgtgc acgctaccta ggctctgctc agaacacagc 6180 acccgggcac cggcgcggac agcggccctt cgacgacacg acacgactgg cgccgggcgc 6240 acggcagttg gtccccggcg gagcggacgg aacggcgaat cggcgcgatg ggcgcggccg 6300 ccggcgagcg gagaaccctc tcacggaaaa gaggcacgac cgtggatgtc ccagtgaagc 6360 aggagtcgcg gcaggaccgg ttcgaggatc aggacgagga ccggttcgcg gcgcaggagt 6420 ccatcgagtg ctcgcggctc ggcgacggga tcgccctggc ggagttctcg ggggcgcacg 6480 agcagaaccc gttcagccgc gcgcggatgc gcgaactcac cgcgttgatg cgggagttgg 6540 acgcggacga gaaggtcagg tgcgtggtgc tgtacggcgg cgccgggcgg tcgttcgggg 6600 tggggggcga cttccacgag gtgtcggagt tcaccggcgg ggacgaggtc aacgcgtgga 6660 tcgacgacat caccgacctg tacaccacgg tggcggcaat ctccaagccg gtgatcgccg 6720 ccatcgacgg ttatgccatc ggtgtcgggt tgcagatctc gttgtgttgt gactaccggc 6780 tcggcagtga gcaggcacgg ctggtgatgc cggagttccg ggtgggcatc gcctgcaact 6840 tcggcggttt catgctggag gccgcggccg gccgcaccgt gatgcagcgc atgctgctga 6900 cctgcgacga gtggccggcc gaacgggcgc tggcggacgg gctgctgcac gagacggtgg 6960 cctcgccccg gctgctggac cgggccctgg agctggcccg gaccatctcc ggctacaccg 7020 ccgaggccgt gcagtccacc cgtccgcggg tcaacgcgcc tttcgtggcc gggctggagc 7080 ggatccgccg cgaggcgaag gagtcgcacc gcagagcctt cgcggccggc gaggcccagg 7140 tgcggatgcg ccgcgtcatc gggcggagct gacctccccg gcgggcgcgg gggtcgcggt 7200 cacccggtac gcgtagtcgt agaaccgcga ctcctcgcgc cacccggtcg cccggtacag 7260 ggcgagcccg gcccggttgc cggtgtccac ggtgagcacc atctcgccac ggccgcgggc 7320 ccgggccgcg gccatcaccg accgcagcag gaaggcaccg aggcgccgac cgcgcatccg 7380 cggcagcacg ccgatctgcc gcaggtaggc ggcgccccgg gtctgcgcca tgcggtcggt 7440 gacgttggcg aaccccaccg gctcgccgtc gagttcgagc agcgcgcgct gggacggatc 7500 ggcccccggg tcggcgccgg tccagcgcag ccactcctcg aagccgtccg gctccatgcc 7560 ggcctcctcg gcggagaagg cacggttctt caccgcgtgg aaggcccgca gccccgcctc 7620 accctccggc acccgcacca ccgccccggg caccgggggc tcccccgccg tcgccccgcc 7680 cagcggcacc gacatccgca ggtacggacg cggggcggcg aacccgtagg cgctgagcgc 7740 gatccgcagc gcggtctccc gttccgacac gaaacacgac agacacacct cgccttcggg 7800 ccgcccggcc gcgatggtcc ggcagcggcg gtgggcgaag tcgagcagtg aggcggcgtc 7860 gtcgggggtg gcgtgcgggg cgagcaggag ttcggcgtcc caggcggagc gccccgagga 7920 gcggctgagc cacaccgcgc cggccacctg tccgtcggag ccggtgagca gcgcggtgtc 7980 gtgttccggg tcgagccccg gggcggccag ccggccggcg atccaggtgg caccgacctc 8040 cacccggccg agcgcggcgc ggtcgcggtc ggcggccagc cggaccaggg cgggcagatg 8100 gtctgcgggg cgtatcggga ccagccgccg tgggctcacc gtccgctctc cggcccggcg 8160 gggtggcggg gcagcgaata gcagtaggag acggcacgcc ggtcgtcctc ggtggtgttg 8220 ggcgccgagg tgtgggcgac gtagccgttg aacagcagcg ccgagccggc cttgcggggc 8280 agggtgaccg gggtgaggcc gggccagatg cgtgcgatgt ccagggacgg ttcgcgcggt 8340 gaggcgaaga tgtcgccggg gtcgatgccg tccggttcgt agagtttgcg ttcccggtgg 8400 gagccgggca ggaagcgcag gcagccgttg tcctcgcggg cgtcgtccac cgcgatccag 8460 atggtgtaga cgtccacgta cttctcgtgc cactcgtcgg ccaggaagat ggcgtcctgg 8520 tgccagggtt tctgggagcc gacccgggag ggcttggccc acaggaagca gtcgtagaag 8580 tcaccgggca ggccgtgcag cggttcgatc agcttctcgt tgaggccgac gaggtcgggg 8640 acggcggcga ggtcggcgga gtgttcgtgg gcgcggccga tgatgcgcac cttgccgggt 8700 atgcactcct tgccggccgc ccgggcggcc catccgccgc cctccccctc ggcctccagc 8760 tgccattcct cggtgctgat gcgcatccgc tcggtgcggc cgatcagttc ggcgcagccg 8820 cggcgcatca cctcgagtac ggattcgggc accaggtcgt ccagcgccac gacaccgtcg 8880 cgccgcagtt cgtcggacag ggcctggatc gactgggtca ccggcatggg ttccacctct 8940 tccggagaac acaaggccag ccgtgctgcc ttggtagatc cctgatcgcc acaactatcc 9000 ggtggcggcc gagggggagg caacgcgccg cccgcagatg agtcgggggt cggccaaaaa 9060 ggcatagcgc gcggcgctgc cgtccgggcc ggtctcactt acgctgatga cccgtcatgt 9120 ggggacaagg accgacccgg gaaccgggcg gcgacaaccg gggtgtgccg atggtgtgtg 9180 cagcgtccag tccggcgggc gccctgctgg tcgactgggg cggtgtgctg acccagccgt 9240 tctacgccgg gatcgccgag tgggccgcgc gggacggggt ggacgccgac gccttccacg 9300 cgttgctggc ccggcacctc ggtccgggtg cgcccggtgg cgcggcggcc tccgtcttcc 9360 accgggtgga gcgcggtgag gtgccggtgg ccgagctgga ggtgacgctg gcggagtcgc 9420 tgcgccgccc ggacggcacc gggccgcccg ccgaggggct gatccagcgc atgttccagc 9480 cgttcaccat ggccggcgcc atggtggagc tggtgcgccg ggtgcgcgcc tcgggggcgg 9540 cggtggcgtt gctctccaac tcctggggcc acacctacga ccgcaccggc tgggacggcc 9600 tcttcgacga ggtggtcatc tcctgcgagg tggggatgcg caagccggag ccggagatct 9660 accggtacac cgcgcggcgg ctcggggtgg cgccgcggcg gtgtgtcttc ctggacgatc 9720 tgggacgcaa cgtgcgggcc gcggcggcgg tggggatgac cgccgttcag cacacctcgg 9780 tggaggagag cagcagggag ctggcccggt tcttcgacgt ctcgccgctg ccggccgggc 9840 gttgacgggg caggggtggc gtggtgctcg ccgcggcccg gcgcagcgcg gcgacgaggg 9900 tgtcgagccg gtcctcggcg gcctcggtgc agtgcagcag ccggcgggcc atgggggaaa 9960 ggcaggtgcc gcggggtgcg ctgtgcacca gggtgcgtcc gcagacctgt tccaggcggt 10020 ggatgcgccg ggtgagggcg ggttgggtga tcagcaggtc ggacgcggcg cggttgaggc 10080 tgccggtgcg ttcgatgacc cgcagcaggt agaggtgttc cgcctcgacc agcgaggagg 10140 ggccctcggc cgtccagtgg cgttcgcaga ccaggaacgg cagcgggtcg cgggggccgt 10200 cgggctcggt ggcggcggac cggccaggcg gcggcgccga caggtcagcg gcgggtaacg 10260 ggaaggtggt ggagcgcaga tagccggggt tgcgttcggc agcgtgctgg acgtagcgcc 10320 gctgcagccc ggtacacagg tcacgggcga gcgcctcggg cagcagcagc ggatcggtgg 10380 cgaggaagag gcggcgcacg acctgctggc gcagcgggcg cagcgcgtac ccggcgtcct 10440 cgaccggggc cgcgcacagc ggggagacca gggcgaagcc gtagccgcgt gccaccaggt 10500 cggcggcggc gctgcgggag tggacggtgc agccgacgcg tggggtgagc ccgtgccggg 10560 cgaaggcacg ggccaggtcc tcgtgggtgg actcgcccac gatggcgacc cattcggcct 10620 cggcgaggtc ctccaggccg agggcgccgc ggccggcgag gggatggccg cggggcaccg 10680 ccacccattg cggctcctcg acgaccaggc gcacgtcggc gccgtagcgt cgcagcgccg 10740 gggtggagcg ggcccaaccg caggcggcgt ccacggcgta gcggtcgaag cgcgaccaca 10800 cgtcctggcg ggcggcgggc accaggtcga agacgacgtc ggggaagccg accgccggct 10860 cctcaccggc ctcgcaggtg tattcggtgg agacggccat ctgcaggacg cgcagtcgcg 10920 ggccgggttc gtcggtgtcg gcggcgttgg ccatggcgaa gtcgatggcg ccgagcaggc 10980 gttggccggc gtgcagcagg gcgtggccct cgtcggtgag ccgggcgccg gtggagcccc 11040 gggagaccag gacggtacgc agccggcgtt ccagccgggt gaggcggcgg ctggcggacg 11100 actgggtgac ccagccctgg cgttgtgcgg cgtgcagact tccgtggtcg gctacggctt 11160 gcaacagtgc tacatccgaa cgtctcagat cgaacattcg ctgctcctgt gcgctgtggt 11220 gccggcttcg ggcggtgggc gaggaggggg gaagcgctcg cacagttgtc gggtccgtaa 11280 ccttcccgtc acgtcagccg gtcaaccgtg cccgcggtgg gggggttggt gccggtggtg 11340 tgcccgttcg agcgggcggc gcgggggaag gcggaaccgg cgcagatccc gagcgcgccg 11400 agcaccgcgg tgccggcgaa gacgagcgtg taggcggcgg ggctcggatg gtcgccggtg 11460 gtgccggcgg cgagcaccat ggagccggcc tggacgccga aggagccgcc gaggctgcgc 11520 agcaggctgt tggtgccgac caccaccccg gtggtgccgc ccggcgaggc cagggtgatc 11580 agctcggtca tcgcgccgcc gaggacaccg gtggccgcgc cgttgagcag cgtgcccagg 11640 gcgagggagg ccatgctgac cggcaggaag gcgaagacca cggcggaggc ggcgaagagc 11700 acggtgccgg tgaccatcac ggcccggggc ggcagcacgc ggcccagccg tccggacagc 11760 agcccgccgc ccagcgtgcc gatctccatc ggcatcatca ccacgatcac accgagcccg 11820 gccaccccga ggccgccggc cgagcgcgga gcctcggcga tggccggcgg gaacgtcccg 11880 gtcacgaaca tcaccaggcc ggtgaggagg ctgaccgcgt tgagtgtcca gatcggccgg 11940 cggctcatca gccgcaggtc catcatcggc gtggtggtgc gccgttccca ggcgagcagc 12000 gcggccccgc tcaccacggc gccggccagc agcgtactgc cggtgaccga gccgatcccg 12060 tcgcgcccgt atctgcccag cgccagcagc accagggcgc tgctgacggc gagcagggtg 12120 agcccggggg cgtcgaggcg ctggccggcc cggcgcgggg tctccgggag caccgccgcg 12180 ccgatgagca gcagcagcgc ggccagcgcc gcgccggtgg cgaacaccca gcggtagccg 12240 tccgggtcgc cctccaccac cccggccagc atgatgccgg cgccgccgcc gaccccgaac 12300 gacgcggaga gcaccccgaa cgggccggcc agcgcacccg ccgggaaccc ctcccgcacc 12360 aggccgaccg cgagcgggaa gaggccgccg gccacgccca tcaccagccg agcggccagc 12420 agcagcccga aggtgtcggc gctcgcggcc accgcgccgc cggccgcgaa gacggcgagc 12480 accgccagca gtacccggcg cctgccgtac aggtcgccca ggcgccccac caccggggtg 12540 gccacgcacg ccaccagcag gtggccggag accacccagc cggtgtccgc cgcgccgacg 12600 ccgaagccgt gccgcaactg ggtgagcagc atcgtcacgg ccagttgcat gagcgcgaac 12660 agcccgcagg cgctggccag tacggccagc gccacggtgc tcgcgccgcg cgccggggag 12720 ccgtgcgccg gtgcgctcac cgctgctcgg tcaggacggg ctcggccggc gaggtgacct 12780 cggcggcttc gaaccggtgc cggtagtggc cgatgcggga gaccgggtag ctggggccga 12840 tggcggcgcg ggcgaacgcc ttgaggtcgc cgggtaccgg ggtgtagcgg ccgttggcgc 12900 cgaagcgctg gtcggccagg cgcatccgga ccgggcgcct gcgcagctcg ccggtggtga 12960 agtagccggg ccagtcggcg gtgtactcgg tggtgcggcc ggccgccggg tcgtagtcgg 13020 ggcgcagcat cacgtcctgc tggaaccgga agacctcggc gaggtcgggg tcgctggtgt 13080 cgtccacgcc gagggcggcc acgaagtcac gcagttcggt gtaggtgcgt tcgaagtcgt 13140 tggcgatccg cagccagccc cagttgtcga tggtccagcc gcgccgcttg ccgtaccggg 13200 cgaggtcggc ggccatgtcg ggctggctgg cgaccaggtt ggccagcggc agttcgggga 13260 tgtcgatgta gtcgtggtac agcttgcgca tccgcaggta gatcgagccg agcacggtgt 13320 cggggcgggc gccgaagtac tgctggagcc gttcgtagaa ggcggtgtag ccgatgtcgt 13380 ggcgttgccg caggtacatc gacagatagc gggtgtagca gccgttgtgc aggaactgca 13440 cggcctggac gaagccgaag cagtcgaccc attcgtcccg ggacatggcg ttggtctcca 13500 tcaccatgtc cacggtctcc gcctcgtcgt ccggggtgcc gggctcttcg acgtagagcc 13560 gcttgggtac ggttcgcagg ccgtaaccgg cgatcttctc gggggtgttg atgggggcgt 13620 tgggcaggat gccgaactcg tagacgcgga tgtcctcgtg gttgccggct tccagcaggg 13680 agccgatgcc gtcccggaag ctgcgcggtg actccagcgg gaggccgagg atgagttcgg 13740 tgtaggtgtg gatgttctcg gtggcgtacc gctgctggag tttgcggtag ttctccaggc 13800 cgatgttctt gcggtcgatg gcctccagca cgtcgaggtc ggtggactgc atggacaagg 13860 tggtgcccat cagcaggtcg gcgtcgtgcc aggtcttgct gatctcgaag acccggtcgt 13920 tggagttctt ggcgaagttg acccggatca gtttgggtgc cccggtggcc gcccgggcgt 13980 cggcgagggc gcgcgcgatc tccaggtcac gggggaggat gccgaagttg gcgtcgcaga 14040 cgaagaggtc ctcgacgtcg tgttcggcga accactcgat ctcctcctgg aggcgttcgg 14100 cgtcgaagag ccgcagcgcg ctcatggtgg ccgagcccca gtcgcagaag gcacacgagt 14160 aggggcagcc gcggttggtc tcccacagcg cgtagaaccg caggtcgcgt tggcggcagg 14220 tggccaccgc gccgtccatc acgcccagca ggtaggggct gggggtctcg atgcggcgcg 14280 gcagccgctc ggccgggcgg ccgggcaccg cctcggtgcc gtggcgtacc gagacgcccg 14340 gcaccctggt gtagtcgggg tggtcggcca gccgctcgat gagcagttcc cggaaggccg 14400 tctcgccctc gccgtgcacg agcacgtcga cgtaggggtg gcgggcgaag aagtcaccgg 14460 gccggtcggg gacgtgcggg ccgccggcga ccaccagcat ccccgggtgg cgttccttga 14520 ccagccgggc caccttcatc tggcggcgga agttccacac gtagcaggag agcgccagca 14580 cgtccgggtc ggtgatcccg gcggccatct cctggacccc gtcgaccagg aacaccggtt 14640 cctggaagtc gtatccggcc gcgacgcgcg gatcctgttc cgcgtaggtg cgcagcagac 14700 cggccaccag gggcaggaac ggcaccgcgt tgaggccgat gaagtacacc ttgcgaccgc 14760 tgcgcgcggc ggggacggtc atgctctcac ggctcctcgg gttcggggct gttgccggct 14820 gcgggcaccg ggcggtgtca tccggtgccg gcgaccgtct cgggctcgcg cgtcggcgac 14880 cagctctcgc gcgggtgcga ccagtcggcg ccgcgtcgca gttcccgcag catctggtcg 14940 aaggcgtcgt cgtcggagta gtagaagacc gacgggtcgc tctccccggt caccccgggc 15000 gcggtacggg cgctggcgcc ggccagcagg tcggccagtt cgccgtagaa ccgctccagc 15060 ggcagccggg tgcggaacag cgagtggtag cagtcgaaga gttcggggtt gtcgctgatc 15120 agcccgagct tggcctcgtc gtacaggtcg gtgcccggca gcggggtgag caccgagaag 15180 ctgggcatgt ccacctggag ttcgtcgacc gtgcggccga gccgggcgaa gtccgcctcg 15240 gaccagtcgg gttgcacgat gaagttggcg cggaccttga ccccgttgcc gtggaagagg 15300 tccagcgcgc gcctggtctg gccggggtcg gtgcccttgc ggtagccggt cagttcctcg 15360 tcggtcatcg actcggcacc caccagcacc gagtccagcc cgatctcggc ccagcgggcg 15420 atcacgtcgg ggcggcgcag cgcggtgtcg gtgcgtacgt acatgtggaa cttcttgcgg 15480 aagcccgcct tgtcgatggc gtcggccagt tccagcatgc ggaccggctg gatgaacgcc 15540 tcgtcgtcga cgacgtagag gttgtcgccg tcgatgtcgg cgatctcggc gagcacccgg 15600 tcgatgtcct tgaccaggta gcggcggtcg gtcatccgcc acagcgagca gaacttgcag 15660 gtgtacgggc agccggcggt gaagcggatg agcgccaccg gccggtagat ggagtggaag 15720 tagcgtccgc ggtggtgggc caggcgggtg cggtccggca tcggcaggtc gtcgagggcg 15780 gacggcttgg ggcgccggtc gcgttcgagc ccggtgcggg cgtcgtaggg ggcgaggccg 15840 cgtaccgggg cgggggtgcg gccggcctcc agttcggcgg cgaggtgggc cagtggtccg 15900 ccgccctcgc cggccacgat ccagtcggcg gcgaacccgg tcagccactc ggcgctgacg 15960 gtcgggtggt ggccgcccag cacgatcggg gtgcccggcc acagccgccg ggcctggtgg 16020 gtcacgtccc gggagacccg gacgctggtg gtgtagggga tggcgacgcc gatcaggtcg 16080 ggcgcctcgt gggtggcggc gtactcctcc agggaggtgt ccacccgcag gtcgtggatg 16140 gtgacgtcgt gggcgccgcg cagggcgccc gccaggtatt ccagcggcag cggctcacaa 16200 cagctgagcc ggtcgctgag gagggcccgc tcgttacgag gccacaccag caagaccctc 16260 atcggatccc tccaactcgt cggtaccggc agcggtgtcg cggaagacct cggtggccat 16320 ctcgtacagc cgccttgcct gggtgtgccg gtcgtcgctg cccagggcgg cggcgaacat 16380 gcggctcatg gcggtgccct cgtggatgcc gcgcttgggg cgccaggcga cctcgtccgg 16440 caggatgccg gtgaccgcgc tgcgcagcac ccacttcgcg gtgtcggggc gcaccttgag 16500 ccggccgcgg atgccgagcg cggtggacat cacctcgcgg gtccagtacg ggtagcgcac 16560 caccacgtcg cgggcgtcgg cgtaggcggg gttgaactcg ttgctgacgg cggtggcggc 16620 ggtctgggcg gcgaccgagc gttcgatccg ggtctcggtg ccggtgccgc cgaggccggc 16680 gaagatcagg tcggcgccgt aaccggagag catcacctgg cgggcgccgg tggcgatgtg 16740 gcccagcagg aagcaggcgg gggcggcgat ctggagggtg agcaggtccc aggtctccag 16800 cgagcggatc atctccggca gcagcgcggt cagttgctcc ggttcgaaga ccagctcgtg 16860 gtgtttgctg ccgagccgtt cggcgaacca ggcggcctgc gcgaactcgt cgccgaacgg 16920 ggtgcccacg gtgtacgtgg acagcgaggt cacctcgcgg gcggcgagcg cggccaccga 16980 ggaggagtcc acgccgccgc tgagcatcac cccggcctcg gtcagcccgg tggcgaggcg 17040 gccgaccgcg tgggtcagcg cgtcgcggac ggcggtgacg gcgcgttcgg ggtcggtctc 17100 ggtgggccgg gcgggcagcc ggtggtagcg gcgggtgagc aggggctcgg tgtcgaaccc 17160 ggccaccgcg agggtgaccg cggtgcccgc ggggacggcg gtgaccccgg cgaaccggcc 17220 gccgggcagc accgcgcggt cgccctcgcc cagcaccgga gcggtgccca gcagcggcag 17280 cagggcgccg gccgaggtgg cgaccagcag ggtgtcgtcg gcgccgcggg cgtagtgcag 17340 cgggcaggtg gcgccgttgt cgctccacag caccgcgcgg tcgtcgcgta ccagcaccgc 17400 gcagaagcgg gagtaggcgc ggaccgtcca ggcgatcagt tcgtccagcg gggcgtggat 17460 cggcgcctgg ccgcccgggg tgagcgggtc gccgtggacc acgaggacgt cggcgccgtc 17520 ccgggtcacc tcggtggcga gcccggtgcc ggcgccgagg tgttgcggga cggcaccctc 17580 cgggcggcag cgcagcagga atccggccat gtcagtagac cccctcgatc cggcgtccct 17640 cggtgaattc ggggctgtac gggtcgccca gccagggcca cgggtagcgt tccgcggccg 17700 ctccgtaggg ctggacgcgg cgggcccggt cgcgttcgag gaagccgggc agcagggcgt 17760 cgtcggtgag ccgccagacg cggacccggc cctcctcgcc gaacggcacc tcgttgccgt 17820 cgtcgtcgac cgcgtccagg gcgatgtgcg gctggcaggg cacgtagacc acgtggtggt 17880 cgtcctccgg ctcgaacggc ttctgccagc tgatgccggt ggtggaggtg ccgtacatgc 17940 cgaccacggg gaccccgggg aagaagtcct cgcgcagttg gcggtgggat tccggctcca 18000 tggtggtgcc ggcgtggacg atggcgcgaa gccccggcag cgcttcggtg ccgaggcgtt 18060 ccggcagcat ctccagcagc cgtgaggtgc agaagagcac cccgatccgc tgggcgcggg 18120 cgacttcggc gacctggtcc cagatgtgct ggacgtagcg gtcataggcg gccgtcatgc 18180 cttcctcgcc gaagatcttc acgatccgcg ggtcgaggtc gacggagaag cacatcccgc 18240 cccggcgttc cgcgaaggcg accaccagcc gtccggtggt gtgcggtccc atcgggccga 18300 cgaagagcca gtcgacgccg cgcggcacgc cgtgcaggtc gaggaactcg tcggagaact 18360 ccaggatgtc ggcccagtaa cgggcgcccc aggtgccgtg tttggcgggt ccggtggtgc 18420 cgccggtctg cgcggcccac agcggtccgc cctcggtgag gacgcggcgc ggcacgaagt 18480 tcgccagtgg cgtgcgccgg gacgcctcct cgaagtgtgc ctggtccggc ccgtcgcgca 18540 agccgatcag ttgctgggcg tccagcatgc cgtgcacctt gcgcagtgcg tcggtgccgt 18600 cgcgccggtc gcgctccagc cagtacgggg tgccgtcctg cgggtcgaag tggagtcgta 18660 cggcccgtcg cacgtcctcg tcggtgatcg gacggagctt ggacggactt ggcatcagca 18720 gtctccctcg tacgtcgctg tcctggcttc cgctcacccg gccgcgcccg ggatgaccgc 18780 cttcttccgg aacaggaagt cggcgaggta gccctcgtgc gggtcacacg ggtggtagcc 18840 gcggtcgtac tcctcggcgc cgaagacctt gtccaccccg ggctcctcgg ccagcgcgcc 18900 gagcagtccg gccgcgtcgc cgaggaccga gacgatcagc gaaccggcgc aggcggccac 18960 cgccttggag cgcggcacgt gggcaacggc cgtgaacggg aacggcagtt cggtgccgaa 19020 gagcggtgac cccgggtcga caaggagcac ggtggggcgc aggaaggcgg cgccgtccac 19080 ctcgacccgc agcggcaccc cggtgacggc ctcggtgacg tcgacggcac cggccgcgat 19140 ctcccgttcg atgcgggtgg cgagggcgtc gcgccgcgcc cggtccggga acgccggtac 19200 ggtggccgcc gggtcgtcca gcggcagcac cggccgggtg gcgaactcct cggcgaggcg 19260 gtcggcggcc tggcgggcgt ccccgagggc gatcaccgag ctgacgttgg tgcacagccg 19320 tccgcagccg gcgaaggcgg cccgggccag ccggggccac gcgtcgtcgg cggcgccggc 19380 gcccaccacc gcccggctgc ggccgaagtg gtaggtcttc gccttgcccg gcggcaggtc 19440 ggcggggacg tcctcgccgg gccagagcac ctggtcggcg aggcggcgca gcgccggggc 19500 gtcgccgtgc accaccgaga cggcgtgctc gggcagcccg gcctcgtaca gcgcctcggt 19560 gagcagcacc ggggtgaacg ggtcgtgccg ggaggtggac agcagcaccg ggcggcgggc 19620 ggcgagcgcc tggagccatt cgatgttgat ggtggggaag ttgtcggcga ccttgaccag 19680 caccgagcgg ccggccgggc gccagctcca gcgggggtgg tggccgccgg tgcggtaggc 19740 cgcgacggtg ccgtccggtg actgggcggc gaggatctcg tccatccggg ccaggtcggc 19800 ggcgacggtc tcgatgccgc gggcggcgcg ccggggaggc agcccgctcg ccgcggagag 19860 ggcggtcagc cacggctgcg cggtgccgtc ggcgacgcgt gcggtgagcg tgtccgcggc 19920 gcggcgcagc agcgcgaacc aggcgtcgtc gtcggtggcg cgcagccgcc gggcgaccgc 19980 ggcggcctcc tgggccatct ggaactggac gagccggccg gccgccccga cccgggccac 20040 cgtctcgccg gtggtgccgg tgagcgcggc cggcctgctg gacatcaccg gccggcgccc 20100 ggcgtaggcc gggacgtcga ggacggcgcc ggcccgctgc gggccggcgt gtccggtggt 20160 gacggtcgtc actggacctc cggtaccagt gcggccggtt cgttcgacag gttgctcgcg 20220 ccgtcgccgt cgagcaggcc gaggcgggtc tgcacggtct ggaggttggc gaggaacgcg 20280 atccgcttgt actggccctg gctgcggctg ggggtcatgt cgtcgtagag cttccacagc 20340 tcgtcgatgg aggcccccat gctggaggtg accgggatgt ggccggtgta gcagtcggtg 20400 tcgctggtct cgacggtgaa gtcgacccgc ttggccatgt ccttctccac ctcctggtgg 20460 aaggggacga agaagcaggg cgagacgagg tcgtgcttgt tcttgccgag ccgggcctgg 20520 agccaggtga tggtggtgcg catcgcctcg tcggtctcgc cggggatgcc caggatcatg 20580 gtggcctgca cgccgatgcc gttgttggtc aggcagctga tggcgcgttc ggtgacgtcc 20640 accttgaccg ggcggccgag ccgcttgagc aggttccagc tcagtgtctc cacgcccacc 20700 agcagccgga agcagccgga ttcgcgcagc atgcgggcca tgtcgtcgtt gatcaggtcc 20760 gggcgggcct tggcctccca ctcgaacttg ccctggagtc cggacttggc gatgccgtcg 20820 cacagctcct gcatgcgcgg gacgtcctcg acgaagtcgt cgtcctcgat gcgtatccgg 20880 tcgaagccgt acacctcgac cagttcgcgg atctcgtcga ccacccgggc cgcgctgtgc 20940 cggcgctggc cgacgcccca ctggtgcttg gagtagcagt acgcgcaggc gtaggagcag 21000 ccgcggctgg tgaccaggtt gccggagcgg ccccgggaga tccgccggta caggtcgagg 21060 tcggccaggt cgcgggcggg cttggggagt ttgtcgaggt tgaccacctg cggggcggcg 21120 ggggtctcca ccacttcgcc ctcgtcgtcg cggaaggtga tgccgcggac cttggcgaag 21180 ttcttccggc cgttcttgcc gaattcgtgg acgagttggg agaaggagta ctcgccctcg 21240 ccgcgcacca ccacgtcggc ggcgttctcc tcgatgagct tgcgggcgat ggggctggcg 21300 ccgacgccgc cgagcacggt gagcgcgttg gggtggcggt ggcgtacctc ggaggcgagc 21360 ttgatgccgt tcttcaggct ggaggtgagc acctggatgc cgacgatgtc cggccggtag 21420 ccgcgcagga actcgctggg ggtggacagc gggcgctgga ggacgaagag ctggtcgtcg 21480 atgaagtgca cgtcggtgcc ggcggtgtcg tggaaggtcc cttcccggag caccgaggcg 21540 agcgacagca ggcccagttg cggagcggag atcgactctc ccgagtacgg tgaccggcgg 21600 gcgttcacga ggagaacttg catgtcaggt ctgcctcctg cggttggaga gccccgggcg 21660 tggcggggcc gaccgccggc agccccgcgc acacggggat tccgtggcgt gaagaagcgc 21720 tcctgcccgg tcggcggctt ggcgccgggg cagcaggacg ggttcgaagc cggcggcggt 21780 tcccgggact tgcgccgtcg gtcagcggca gttgggaaga agtcttcacc agatgaacat 21840 gggccgtaat gcccggtcca atgcctttac cgggtcgcgc caatgccgtg aggacatggg 21900 atcggtctgg aacgggcggc catgcccgcg ggccatcacc gcgatgcgcc ggggacactc 21960 cctgcggccg ggttggtgtg gcagcatcgc tgaggccaga tcacgtgcgc tcgtcggatg 22020 gtgatgggaa ggtgcggatg accgcctcac atgacacggc agacgccacg gaccggaccg 22080 tcggttccac gtccggcgaa cgagcggcgt tcgcccgtga cggagtggtg cgttggggcc 22140 gcctgctgac gcctgatcag atcgacgcgc tgcggtcctc ggtggagcgt gccttcttcc 22200 gcgacggcca ccccgccgac ggggtacgcg atctgtccga acgccagggc cgcccgctcg 22260 acctggccct gctgcacaag atcaacctgt ggcggaccga cgaggcgtgc gcggcccagg 22320 tggccagggc cgacctggcg gaccgggccg aggcgctgct cggcgggccg gtacggctct 22380 accgcgacca cgtcttctac aagccgccgg gcaagggcga ccgcagccgc atggtgctcc 22440 accaggacaa ccgctactgg cacctggacc cgccggaggc catcacggtg tggatggcgc 22500 tggacgacgc caccgtggag aacgggtgcg tccactacgt cctcggcagc caccgccacg 22560 gccgggtgga gcacgtgcgt cccgaggagg gcgcggtgat gatcgaggcc cgtaccgagc 22620 aggagccggt ggcctacccg gcccccgccg gggacgccct ggtgcacagc gtcaacacgc 22680 tgcacggctc ggggcccaac ctcagcgacg gaccgcgccg cgcctacgtg gtggtctacg 22740 tgcgcgacgg ggtgacgatg cgcggcgagc cgatgacctc gttcccgctc gtcggcgacc 22800 tggtccgcgg cgggtgaggg cgcgccccgt caccgcgaca ccgagccgcc cgcaccggac 22860 cgccctccgg tgcgggcttt cgccttggcg cgtacggaaa ttgatggccc gtcagcgacc 22920 gaaaccgccg ccgtaccggc gcagcgcgtc cggcagctcc tcgatccggg aggtgtccca 22980 cggccgcccc cagccggcca gccgcatcag ccagtcgacg atgctcccgg tgaaccccca 23040 cacgaacagc tcccgcacca ggaacccggg gctgatgtaa ccgtcctggt agcgcacccg 23100 gaaccggttg gcggggtcgg cgaactcggc gagcggcacc cggtgcaccg agaccacctc 23160 gccgcggtca ccgcgcggtt cggcctcggc gccccaccag ccgagcaccg gggtgacccg 23220 gaagtcggtc caggcgatgc gcagcgggcg cagggtgccg gccaccgcga cgcctgccgg 23280 gtcgagcccg gtctcctcgg cggattcgcg cagcgcggtg tggaccacgt cgcggtcgcc 23340 cgcactcacc gatccgcccg ggaagcacac ctcgtcgggg tgggagcgca gggtgcggga 23400 gcgtcgtacg aggagcaggt cggtcccggc gtcgccggtg ccgaagagca ccagcacggc 23460 ggaggggcgg ccccgggcgg ggtcgtcgag gaggtagcgc accagctcgg gagggctgtc 23520 gtcggccgct tgccgggcca ggccggtcag ccaggtcgga acatcagttc ggtgtcgtgg 23580 gtacacgcga tcgaggtcca ccgggtcagc gtaggcaccg gggccgtccg ccatcaccct 23640 gatcgccgaa aaagacactc ccccgtggac tcccggtgcg cggggtcccc ggggccctgc 23700 catgatgggc ggcgcagcca ccgagagtga ggtcgcgtca gccatgggta gtcaccgtct 23760 cctccgcgcc cgcgccggga ccgccggggc cggccccagc agacgcgggc tgatcggcac 23820 ctcgctggcg gggatctccg ggctcgccgc cgggttcggc tccctcgggg cgcgtccggc 23880 cgccgccgcc cggcccggtc cggtcggcgg cacgacccgg ctgcggtggt tcggcaccaa 23940 cgcctgggag atcggcttcg gcgggcgcac cgtgctggtc gacccgtggc tgacccgctt 24000 caccgcgcag cggccggacg gacgggtgga cccggacacc ccgctcaccg tcgaccattc 24060 cgccgtcgac cgccacctgc gcgccgccga tctgatcctg ctcacccacg gccactacga 24120 ccacatcggc gatctgccgt acgtgatgcg gaagttcccg tccgccccgg tggtggccac 24180 cgagacccac gcccatctgc tcaccgccat gggcgccccc accgaccggg tcatctgggc 24240 ccgtggcggc gaatacctgg acttcggcga cttcgcggta cgcgtcctgc ccagcctgca 24300 cagcatgggc cccgaccacc gctacttcgc ccccggcacg ctcaccgcgc cgccgcgccg 24360 cgcccgtacc gtcggcgacc tgctggaggg cggcacgctc gcgtaccaca tcacctcgga 24420 cagcggggcg agcgtcgtca acatcggcac cgccaacgtc atcgagcggg agctgaccgg 24480 gctgcggccc cacgtggcca tcgtcgcggt gccgccgtgc ggggccaccc accgctatct 24540 ggagcgggtg ctcaccgcgc tcggccatcc gccgcacgtg atccccaccc accacgacca 24600 gctcgacacc ccgctgttcc ggccggccag cgtggacccc gggcagatgc gttccttccg 24660 cgaccaggta cgcgcgctcg gcccggggtg cgcggtgacc gaaccgcagt actgcgacgc 24720 gttcacgctc tgatcgcgga tcccgtgcca cgggggtgtt cccgggccgc acggtgtgct 24780 ggagtggacc ccgaggccgg atcaagggcc cgcgggctga agggagttca ccgggtgagc 24840 gcgaacagcg ggggcatcgg cggcgtgccg ggtccgcaca acgggctgac cgacgtaccc 24900 ggggtgcggg tcggccacgc cgggcgtacc ggggacggct ggctcaccgg ggtcaccgtg 24960 gtgctcgctc cgcccggcgg tgcggtggcc gccgtggacg tccgcggcgg cggccccggc 25020 acccgggaga ccgacgccct cgatccgcgc aacctcgtgc agaccatcga cgccgtggtg 25080 ctcaccggcg gcagcgcctt cgggctggac gcggcgggcg gggtggcggc ctggctggag 25140 gaacagggcc gggggttccc ggtcggcgcc gacccgtccc aggtggttcc ggtggtgccc 25200 gcggcggccc tgttcgacct gggccggggc ggtacgtggc gggcgcggcc ggacgccgcg 25260 ctgggccggg ccgccgtcga ggccgccgcc gcccgcccgg agggtgaccc ggtggagcag 25320 ggcggggtgg gcgcgggcac cggcgcggtg gtcggcgggc tcaagggcgg catcggcacg 25380 gccagcgtgg tgctggactc cggcgccacg gtggccgcgc tcgccgccgt caacgcggcc 25440 ggttccgcgg tggatccggc caccggcgtg ctctacggcg cccgtaccgg actgcccggg 25500 gagttcgccg gatacggggt gccggacgcg atcggcgccg acacgcacgc ccgggcgcgg 25560 gcacggctgg ccgaggccgc cgaggagacc gcccggcgcc gggccggcgg cgccgccacc 25620 ctcaacacca cgctcgccgt ggtcgccacc gacgccacgc tcacccgcgc ccaggcccag 25680 aagctggccg gcaccgcgca cgacgggctg gcccgggcgg tgcgcccggt gcacctgctc 25740 tccgacggcg acaccgtctt cgcgctctcc accggccgcc ggccgctcct gcccgaccgg 25800 ccggacgcca cggcggcccg cgccttcggg gtccacctgg aggccggcgc gctcaacgag 25860 gtgctggcgg ccggcgccga cgtcctcacc cgcgccgtgg tccacgccgt cctggccgcc 25920 accggggtgg acacccccgg cggggtccac ccgtcctacc gggagctgta cgcgcgtccc 25980 tgagccgtgc ccgaagccct gccgccgtac tcgaagccgt gaccagccgc ttcgttgacc 26040 ggccaactgc cgctgcctac actgcacttg acgaatcctt gacacaggct tgaccggcct 26100 gtgccggcgg tcccgccgcg ttcgcgggtt tggggggatc cactgatgga cgcagacgac 26160 tgttgggcgc gggcgggcac cgtgcggatc cgcctgctcg gcccggtgga gctggcctgc 26220 ggcacgcggc cggtgccggt gaccgggcgg cgccagttga gggtggtggc cgcgctcgcg 26280 ctggaggccg gacgggtgct ctccaccgcg gggctgatcg cctcgttgtg ggcggacgag 26340 ccgccgcgca ccgccgcccg gcagctccag accagcgtgt ggatgatccg ccgggcgctc 26400 gcctcggtgg gcgcgccgca gtgcgtcgtc cgctccaccc cggccggcta cctgctcgac 26460 ccggcccact acgaactcga cagcgaccgg ttccggcacg cggtgctgac cgcccgggag 26520 ttgcagcggg acgggcggct ggcccaggcc cgggcccggg tcgacgaggg gctggcgctg 26580 tggcgcggcc ccgccctcgg cgcggcggcg ggcgccggac tccagccccg ggcccgccgg 26640 ctggaggagg aacgggtctt cgccctggag cagcgcgccg ggctcgacct cgcgctcggc 26700 cgccacgaga cggccatcgg cgaactcctc gacctcatcg cccagcatcc gctgcgcgag 26760 gcggcctacg ccgacctgat gctcgccctg taccgttccg gccgccagtc cgacgcgctc 26820 gccgtctacc gcagggcgca gcgggtgctc gccgacgagc tggccgtccg ccccggcccc 26880 cgcctcgccg gcctggagcg ggccatcctg cggcaggacg agtcgctgct ggccggcgcg 26940 gcggtgccct gaccggcccg tcccggcggg gggcgggggt caggggcgga cgtaggggcg 27000 cgtcatgacc tccatgttgt gtccgtccgg gtcggcgaag tacgcgcccc ggccgccgaa 27060 cagcccgttg acgcggcccg gttcggtgtg cgcggggtcg gcgtagtacg tcacgccgac 27120 ggtctccagc cggtcgatca cggcgtcgaa ccggtcctcg gggacgatga aggcgtagtg 27180 ctgcgactgg atcggctcgt cgcgcttctc gtagtagtcg agcgtcaccc cgttgccgag 27240 gtcgacgggg aggaacggcc cgaacggctt gccgacctcc aggccgagga tcgcggcgat 27300 gaactccgcc gacaggtagc ggtcggaggc gtagacggcg gtgtggtcga ggcggacggt 27360 cgcggtgggc gacgcggagt cgtgcggtgt catcaggtgt ctctccagtc ttcggaaact 27420 gcgggagcga ggcgccacgc gtgggcgccg gaaacgaaga cacggaagac gggcgggcct 27480 cgtccccacc ccggcgtcaa gccgaggccg ggaccctcac tcgtgcgtgg cccaaggccg 27540 acccggcagt cacgtccgtg atcataacgg cggtccggac gcccggacaa cgccgttacc 27600 gggcgcgggg cggtcagccc ccggacgcct gcggggggcg gcgcagcggg ccccagtcgc 27660 cacgctgccg ggcgacctcg tcgcgggcct cgtggatcac ctcggggtcg atccaggcga 27720 tcgggcgtac gtcggtgagc agcggttcgt tgtcggggcc gcgtcccacc tcccggccgc 27780 gcagcaccca ggggcggacc ccgggaccga tgtcgtggcg caggtggcag tagtcgtaca 27840 ggcggcgggc cacccacagc cggagcgggc ggccggccca ccagtcgtcc acgtcgagcg 27900 ggttcgccga caggccgggc agcgagatgc cggtgaggct gtcggcgctc ccggtctccc 27960 gcaggtcgta gcgggggccg cgggaccagc gcacgtacag cccgcggctg ccgtcggcga 28020 gccgcgcgag gtcgtcgagg ctgctgagca cgggcagccc ggccgaagag gtcacaggcg 28080 acctccggcg ggcgggtacg gccgaccgga catgtctgcc gcgtaccccg gaccacgccg 28140 gtgacacccg gcgcacccgt cccgggcggt acgcccgccg gggcggtacg ggtggccgcc 28200 ggaacgcggg gtaggcgcgg accatgaaca ctctcgcatg gtggttacgg ctgacggtcc 28260 tggcggtggc gggcggcgcg gtcgccctgc tggtacagca ctggacggac gggcgcccgt 28320 ggccggaggc gggcgtcccc gctgcgctgc tggtcgtggt ggcgctgctg atgggggtgg 28380 tctcccggcg gtcgcggcgc gatctgtggt gacaccccgg ggcggcggct acgcgccggg 28440 cgaacaccgg cggcgtcccg cgctccgcac ggcacagtcg gatcatgacg aaccgaacag 28500 ccgtactctc cgacatccac ggggtgcttc ccgcactgga agccgtgctc gccgagcccg 28560 aggtgcgggc cgccgaccgc gtcgtcctca ccggtgacat cgcctgcggc ccgcaaccgg 28620 ccgaggtgct cgacctgttg accgcgctgg gcgaccgggt gacctgggtc gccggcaacg 28680 ccgaccgcga actggtggag ttccggcgcg gggtacgcga gacgatcccc gaccccatcg 28740 gcccgtgggc cgcgcggcag ctccgccccg accacctgga gctgctggcc tccctgccgc 28800 tttcggtgcg gctgccggtg gccgggctgg gcacggtgct cttctgccac gccacaccac 28860 gggacgacga ggaggtggtg gtggtcgact cgcgtccgga ccgctggcgt gaggtcttcg 28920 acggcctcgg ccccgacgtg gacgccgtga tctgcggcca cacccacatg cccttcgtcc 28980 gcctcgccca cggccgcctg gtggtcaacc ccggcagcgt cggcatgccc tacggccgct 29040 ccggcgccca ctgggccctc ctcggccccg gcgtcgacct gcgccgcacc ccctacgaca 29100 ccgacgccgc catcgcccgc ctcacccgcg actgcggcta ccccgccatc gccgagtggg 29160 ccgactacta cgtgcgcgcc cgggcgacgg acacggaggc gctggcggcg ttcggcccga 29220 gggacggacg cggggcggaa gggtagtcca ccgggggcgc ggggcggtcg gggtcggggc 29280 cgccgggtgt gcgggacgat cggcgctggg gcgcggggcg ttgtcggtgg ccggtgggat 29340 gctcgccgtc atgacgccct ggaccctcac cgccatcgaa cgtgccctgc gcgccagttg 29400 ggccgcggac acctgctccc ccgacgatct ggcccgcgcc ccgtggtccc cgggcaaccc 29460 ggcgtggggg cactgcgaca tcaccgcgct gctcgtcaac gatctgctcg gcggtgacct 29520 ggtgtgcggc gaggtacggc tcggtacatc agttccggct cgggtagagc atcgtcgcgc 29580 cgcgcctggt acgccgtccc ccggggccga cccggcatcg ctgggcggaa tacctgctgc 29640 tgcgcgagcg ggtggtcggc aggctcggcg tgctgcccga ccctgcgggg accaactcca 29700 cacagtgaac aactcgttca catcaacccg ttgacaatgc ccgcaaccga acacatgatt 29760 gactcatgcc tgagtccatc gaagatccgt tcaccccgcc cagccccgag caggcgcgcg 29820 ccgagcgcgt ggccacctcg ctgttccgga tagccgagcg gcacgccgcg acggaggagc 29880 ggcggcggcg tcagacgcat ccgtacgtgc tcgctccgca cgaggcggtg cggctggtgg 29940 ccttcctgct gagcggggcc gcgcagcacg aggaggacga gccggaggtg gaccgcgcgg 30000 atctgctggc cgcgctcacg ctgctgccgg cggcccgcgc cgacctggac gagatcgagg 30060 ccggcctgct caagatggcc cggggccggg gcctcacctg gccggagata gccttcggcc 30120 tcggcctcgg caccccgcag gccgcgcgcc agcgctacga acgcctctcc ggccgcatat 30180 ccgccgaccc cgagtgacca ccggccgccc ccggcgccac cgggaccgtc cagaccgcct 30240 ttaaggaaga tttacggtcc cgttggcacc gaaagatccg tcttcgcccg ggcgtggttg 30300 tggaacgacg cgctgattgg ggcgagttgg ccggttcccg gccggttatg cgcggccttg 30360 acgccctggt ggcgcggtgg ttccctcagt ggccgagtga cgcaacgtcg cgcttgcggc 30420 cccgggtgcc cacgacggca cccgcgccgc agccgctgga agccgcaacg tccgcaatcc 30480 gcactccacc cggtccacgc agcaagcaag gcgcagcagc accgcccacc acgggcaacg 30540 caccggtgac gcgcggggga cggcgcgtac ccgcgacggc acggcatgcc gcggagccct 30600 gcccgcacct ccccgccgac gacttcaccc acgcccgcgc gcgtcaccgc gcgggcgcac 30660 ccggcgctgc ccccggccca cccaggagga cgccatgttc caccgcatca gccggcccgg 30720 ccgaggatta cgcgacgggg ccggaacggt cacacgcggc cgaagacacc gcccggtacg 30780 tgggccgggc gagcggtcgc ggtgttcgcg gcccgcctcg gccctggccg tggcgctgac 30840 gctggcgctc accgcggggg tggtctcccc cgccatcgcc gcgacgacgc ccagagccgc 30900 cccgtccgcc gctcccccgc cgcccgcgcc gaccaccgcc gccggcgacg tgctggtcaa 30960 cggctggggc gacggcgccg gttaccacct ggacgtcgcc accggcagcg gcggctacga 31020 ctggcgtgag ctggccgtgc tgcgcccggc gggcatcgac gactcgtcct ggacgggcta 31080 ccagtgcgtc tccggcgacg ggcggtacgc ggcggtggcg atcctgcccg cgtccgcggt 31140 gaacctggcc gtcgcccgcg accacggtgc cttcgcctac tccgtcgacc tgcgctccgg 31200 cgcggtcaag ccggtggcgg cgggcgtggc gctcaagtac cacaccccgg ggtgcggcac 31260 cggcgacacc gccgagttca ccatcgaccc gggcaacgac cagcgggcca cccaggtgct 31320 ctcggccgat ctgccctccg gacgcctcac ccacgtcacc accgtgcccg gccaggtgac 31380 ctccgtggtc cccgccggtg acgggccggt cggggtgctc ggcggcgaac tggtgcggat 31440 accggaggac ggcggccgga cggcacgccc ggtcgcgctg gcgtcggtcg gcgggctcgc 31500 ctacgacctg cgtccggcgg ccggcggcgg cgtggacttc gcggtgcaac gggccgcggg 31560 ccgcagctcg ttgatcgtcc gggagcgctc cggacacctc accacgctgg gcgagggcac 31620 ccacaccggt ctgcggctga tgcagggcag ggcgggccac gccctggcgc tggaggccac 31680 ccgcctggtc ccgggcagcg gggtgcgcgc cgtcgccacc cgtggtctgc cgggtgccgc 31740 caccggtgtc tcgctggacg gcggcgcggt gctgggcctc ggcgccagga ccgccgcgtc 31800 ggcgccactg gtgctggcca cccgcaccgg caaggtgctc aagcgctccg ccgcgccctc 31860 ggcccggcgg ccggacaccg tgctgccggt gccgccgccc ggcgcgttcg gcggtgccgc 31920 gggcgggctc accccgtcgt cggcgggcgt cagggggacg gtctccccgc tgaccgcgac 31980 gcccaagtgc gcggtgggcc gcaacgagga gaaccggcag gtgatgcagc ccggcacggc 32040 ccaggtgtcg tgggcggtgc agatggccga gcaggggctg ctgaccggct cggcgtacca 32100 gcgccccgcc aacttcgcca acctggggct cgtcgcctac tcgcccaacg gcgacttcgg 32160 caaggtggcg ctccaccacc cgtccggtga cagctgggac tcggtgccgc gctcggtgta 32220 ccaggccatc gtggcccagg agagcaacta cagccaggcg tcctggcact cgctgccggg 32280 catcccgggc aacccgctga tcgccgacta ctacggcgcc ggcggatcc 32329 <210> SEQ ID NO 2 <211> LENGTH: 250 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 2 Met Ile Pro Arg Ser Phe Pro Ala Leu Gly Asp Arg Gly Gly Gly Ala 5 10 15 Arg His Arg Pro Ala Asp Arg Arg Pro Asp Arg Ala Ala Pro Pro Gly 20 25 30 Gly Pro Ser Ala Gly His Pro Leu Pro Ala Phe Leu Arg Ala Arg Arg 35 40 45 Leu Arg Ser Gly Leu Ser Gln Glu Gly Leu Ala Trp Arg Leu Asp Val 50 55 60 Ser Thr Arg Thr Val Ser Asn Trp Glu Arg Gly Gln His Gly Val Asp 65 70 75 80 Pro Arg Arg Val Ala Asp Leu Ala Ala Ala Leu Ala Leu Thr Arg Glu 85 90 95 Glu Glu Arg Glu Leu Ala Gly Leu Ala Gly Ser Arg Thr Pro Ala Ala 100 105 110 Arg Pro Ala Pro Ala Pro Glu Thr Pro His Pro Gly Asp Pro Ala Gly 115 120 125 Phe Ala Arg Glu Trp His Arg Gly Phe Arg Asp Val Gly Met Pro Ala 130 135 140 Tyr Leu Arg Asp Pro Ala Trp Arg Leu Leu Ala Cys Asn Ala Ala Tyr 145 150 155 160 Thr Arg Leu Phe Ser Gly Val Ala Arg Val Pro Glu Ala Ile Pro Arg 165 170 175 Glu Asn Leu Ala Arg Phe Ile Cys Leu His Pro Asp Ala Pro Arg Leu 180 185 190 Leu Ala Asp Trp Tyr Glu Gly Trp Leu Val Pro Leu Leu Cys Glu Ile 195 200 205 Ser Asp Asp Leu Arg Ala Ala Pro Pro Arg Ser Pro Leu Tyr Ala Leu 210 215 220 Leu Lys Ala Val Leu Ala Arg Pro Glu Ile Ala Arg Ala Trp Arg Thr 225 230 235 240 Glu Val Pro Ala Arg Ala Ala Ala Arg Ile 245 250 <210> SEQ ID NO 3 <211> LENGTH: 296 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 3 Met Thr Asp Ala Gln Pro Ser Gly Pro Val Val Glu His Gly Arg Gly 5 10 15 Asp Leu Thr Ala Glu Glu Arg Arg Gln Lys Leu Ser Phe Leu Arg Glu 20 25 30 Lys Arg Asp Ser Val Asp Arg Ser Ser Phe Glu Ala Arg Tyr Pro Val 35 40 45 Glu Val Pro Arg Arg Leu Pro Gly Arg Gly Arg His Ala Pro Gly Leu 50 55 60 Thr Leu Val Glu Met Gly Arg Leu Leu Gly Leu Arg Asp Gly Ser Trp 65 70 75 80 Tyr Ala Asp Leu Glu Arg Gly Gln Val Asp Asn Ala Pro Val Asp Arg 85 90 95 Leu Phe Lys Val Ala Glu Leu Leu Asp Leu Thr Pro Arg Gln Tyr Glu 100 105 110 Phe Leu Cys Val Tyr Ala Cys Arg Pro Lys Pro Gly Tyr Pro Ala Ala 115 120 125 Gly Leu Pro Gly Gly Tyr Arg Glu Val Leu Asp Leu Tyr Gln Gly Pro 130 135 140 Ala Tyr Phe Gln Asp Ala Gly Trp Asn Leu Leu Arg Pro Lys Met Tyr 145 150 155 160 Asn Ala Ala Ala Glu Ala Leu Phe Asn Gly Ile Pro Asp Asp Phe Asn 165 170 175 Phe Ile Arg Trp Val Leu Leu Glu Arg Ser Val Arg Arg Pro Pro Glu 180 185 190 Gly Gly Arg Arg His Ala Trp Leu Pro Asp Phe Trp Gln Val Trp Ala 195 200 205 Pro Arg Ala Leu Pro Val Val Arg Ala Ala Tyr Val Ala Arg Pro Asp 210 215 220 Asn Ala Thr Leu Ala Arg Leu His Ala Asp Leu Ala Ala Asp Pro Glu 225 230 235 240 Ile Gly Pro Ile Tyr Gln Gly Arg Leu Pro Pro Tyr Pro His Thr Asp 245 250 255 Gly Asp Leu Arg Pro Phe Val His Gly Ser Thr Gly Glu Arg Gly Met 260 265 270 Val Arg Ile Asn Val Leu Thr Pro Arg Gly Ser Asp Asp Thr Leu Met 275 280 285 Leu Leu Asn Trp His Pro Gly Ala 290 295 <210> SEQ ID NO 4 <211> LENGTH: 259 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 4 Met Asp Leu Arg Met Ser Gly Lys Thr Ala Val Val Thr Gly Ala Ser 5 10 15 Arg Gly Ile Gly Leu Ala Val Val Arg Thr Leu Thr Gly Glu Gly Val 20 25 30 Arg Val Val Gly Ala Ala Arg Thr Val Thr Ala Glu Leu Lys Asp Ala 35 40 45 Gly Ala Val Pro Val Ala Val Asp Leu Ser Thr Pro Glu Gly Cys Ala 50 55 60 Glu Leu Val Gln Arg Ala Leu Ala Glu Leu Gly Gly Ile Asp Leu Leu 65 70 75 80 Val Asn Asn Ala Gly Gly Gly Asp His Phe Thr Ala Ala Gly Phe Leu 85 90 95 Thr Ala Asp Asp Glu Ile Trp Glu Arg Ser Trp Ala Leu Asn Phe Phe 100 105 110 Ala Pro Val Arg Leu Ile Arg Ala Ala Leu Pro Ser Leu Ile Glu Arg 115 120 125 Arg Gly Ala Ile Val Asn Val Ser Ser Ile Gly Ala Arg Asn Ala Thr 130 135 140 Gly Pro Ile Asp Tyr Ala Thr Ala Lys Ala Ala Leu Asn Thr Leu Gly 145 150 155 160 Lys Ala Leu Ala Ala Glu Phe Gly Pro Arg Gly Val Arg Val Asn Thr 165 170 175 Val Ser Pro Gly Pro Thr Arg Thr Pro Val Trp Glu Asp Pro Asp Gly 180 185 190 Tyr Gly Ala Gln Gln Ala Ala Leu Gly Gly Gln Glu Leu Ala Asp Tyr 195 200 205 Val Ala Arg Val Pro Ala Arg Ser Gly Gln Leu Thr Gly Arg Leu Val 210 215 220 Glu Pro Gly Glu Val Ala Asp Leu Ile Ala Phe Leu Gly Ser Asp Leu 225 230 235 240 Ala Ala Ser Val His Gly Ala Asp Tyr Val Ile Asp Gly Gly Ala Leu 245 250 255 Lys Thr Val <210> SEQ ID NO 5 <211> LENGTH: 360 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 5 Met Ala Arg Leu Thr Arg Ala Glu Thr Gln Glu Arg Asn Arg Asp Lys 5 10 15 Val Leu Asp Ala Ala Arg Glu Glu Phe Ala Glu Arg Gly Tyr Arg Asp 20 25 30 Ala Arg Ile Asp Ala Ile Ala Glu Arg Ala Gly Leu Thr Arg Gly Ala 35 40 45 Val Tyr Ser Asn Phe Pro Gly Lys Arg Ala Leu Tyr Phe Ala Val Leu 50 55 60 Ala Ala Leu Ala Glu Arg Val Pro Glu Gly Pro Pro Pro Arg Pro Val 65 70 75 80 Arg Ser Gly Gly Asp Ala Leu Ala Ala Phe Ala Arg Ala Trp Val Ser 85 90 95 Arg Leu Pro Pro Ala Gly Asp Asp Gly Pro Gly Pro Ala Arg Leu Ala 100 105 110 Met Asp Leu Met Pro Glu Val Ile Thr Asp Ala Ala Thr Arg Arg Pro 115 120 125 Phe Ala Gln Leu Leu Lys Leu Asp Ala Ile Leu Leu Gly Leu Ala Leu 130 135 140 Glu Arg Leu Glu Pro Ala Gly Arg Pro Ala Arg Arg Met Val Arg Val 145 150 155 160 Ala Glu Ala Val Leu Thr Ala Leu His Gly Thr Ala Gln Leu Ala Ala 165 170 175 Ala Ala Pro Gly Phe Leu Asp Pro Leu Asp Ala Val Arg Val Cys Glu 180 185 190 Arg Leu Ala Gly Leu Pro Leu Asp Asp Asp Pro Pro Pro Ala Pro Gly 195 200 205 Leu Pro Pro Val His His Val Asp Glu Pro Trp Ser Pro Pro Pro Ala 210 215 220 Thr Asp Ala Val Thr Gly Asp Pro Leu Pro Ala Asp Gly Glu Pro Asp 225 230 235 240 Gln Val Val Thr Val Leu Gly Leu His Arg Leu Glu Ala Ala Glu Asp 245 250 255 Ala Val Arg Ala Ala Pro Pro Asp Thr Pro Val Thr Ala Val Leu Val 260 265 270 Thr Ala Asp Pro Gly Glu Leu Gly Ala Leu Ala Arg Leu Ser Val Ala 275 280 285 Glu Leu Cys Gly Cys Leu Arg Gln Ala Phe Pro Ala Ser Ala Arg Pro 290 295 300 Pro Leu Arg Val Val His Asp Pro Ser Gly Ala Phe Ala Ala Ala Ala 305 310 315 320 Gly Val Pro Ala Val Asp Asp Arg Thr Glu Thr Ala Ile Arg Leu Ala 325 330 335 Ser Ala Arg Val Thr Ala Arg Ala Gln Gly Pro Gly Ala Ala Arg Ala 340 345 350 Val Ala Ala Thr Pro Arg Arg Gly 355 360 <210> SEQ ID NO 6 <211> LENGTH: 212 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 6 Met Glu Pro Met Leu Thr Thr Ala Leu Ala Phe Leu Gly Ala Cys Val 5 10 15 Leu Ile Ala Ala Ala Pro Gly Pro Ser Thr Met Leu Ile Ile Arg Gln 20 25 30 Ser Leu His Ser Arg Arg Ala Gly Phe Leu Thr Val Leu Gly Asn Glu 35 40 45 Thr Gly Val Leu Thr Trp Gly Val Val Ala Ala Leu Gly Leu Thr Ala 50 55 60 Leu Leu Ala Ala Ser Arg Thr Ala Tyr Asp Val Met Arg Ile Gly Gly 65 70 75 80 Ala Val Val Leu Val Trp Tyr Gly Val Gln Thr Leu Arg Ala Ala Arg 85 90 95 Arg Gly Glu Ala Arg Pro Ser Ala Ala Asp Asp Glu Ala Ala Val Val 100 105 110 Pro Arg Ser Gly Trp Lys Ile Tyr Arg Ser Gly Leu Leu Leu Asn Leu 115 120 125 Ala Asn Pro Lys Ala Ala Val Phe Ala Met Ser Phe Leu Pro Gln Phe 130 135 140 Val Pro Ala Gly Ala Pro Lys Leu Pro Val Ile Thr Ala Leu Ala Ala 145 150 155 160 Phe Gln Ala Leu Phe Glu Val Gly Tyr Tyr Gly Met Tyr Val Trp Phe 165 170 175 Val Gly Arg Met Lys Arg Val Ile Ser Arg Ala Gly Val Arg Arg Arg 180 185 190 Leu Glu Gln Val Ser Gly Gly Val Leu Val Leu Leu Gly Ile Arg Met 195 200 205 Ala Val Glu Ser 210 <210> SEQ ID NO 7 <211> LENGTH: 363 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 7 Val Thr Leu Pro Thr Glu Thr Trp Ala Val Arg Ile His Arg His Gly 5 10 15 Gly Pro Glu Val Leu Val His Glu Arg Leu Pro Leu Pro Pro Leu Gly 20 25 30 Pro Ala Asp Val Leu Val Ala Val Asp Thr Ala Ser Val Ser Gly Trp 35 40 45 Asp Val Lys Tyr Arg Arg Gly Leu Pro Pro Gly Ala Arg Leu Pro Gly 50 55 60 Arg Glu Arg Tyr Arg Leu Pro Leu Gln Leu Gly Arg Glu Ala Ala Gly 65 70 75 80 Thr Val Leu Ala Thr Gly Pro Glu Ala Ala Gly Arg Phe Arg Pro Gly 85 90 95 Asp Arg Val Val Ala Val Val His Pro Glu Asn Pro Arg Ala Pro Glu 100 105 110 Thr Val Arg Gly Leu Gly Asn Leu Ser Thr Gly Ile Ala Leu Pro Gly 115 120 125 His Gln Ala Pro Gly Gly Tyr Ala Arg Tyr Leu Ile Cys His Gln Asp 130 135 140 Met Trp Leu Pro Leu Pro Ser Gly Val Asp Leu Glu Gln Ala Ala Val 145 150 155 160 Thr Leu Trp Pro Tyr Ala Thr Cys His Arg Val Leu Arg Asp Arg Leu 165 170 175 Arg Val Ala Leu Gly Glu Thr Leu Leu Val Cys Gly Ala Thr Gly Ala 180 185 190 Met Gly Leu Ala Ala Leu Arg Leu Ala Arg Leu Thr Gly Val Arg Val 195 200 205 Ile Ala Met Thr Arg Tyr Arg Ala Lys Glu Arg Ala Leu Arg Thr Ala 210 215 220 Gly Ala Asp Glu Val Val Val Ala Gly Asp Pro Arg Gln Ala Cys Glu 225 230 235 240 Ala Val Arg Ala Leu Thr Gly Gly Glu Gly Val Asp His Ala Val Asp 245 250 255 Phe Thr Gly Ser Ala Ala Leu Leu Arg Leu Ala Val Asp Ser Leu Arg 260 265 270 Leu Gly Gly Arg Leu Cys Pro Ala Ala Thr Gln Arg Pro Pro Gly Pro 275 280 285 Leu Pro Val Thr Thr Gly Asp Leu Thr Arg Leu Glu Ile Thr Val Tyr 290 295 300 Gly Ile Arg Gly Ala Arg His Arg Asp Ala Leu Arg Val Leu Ala Leu 305 310 315 320 Leu Gly Asp Gly Ser Leu Pro Ala Thr Pro Ile Ala Ala Arg Phe Pro 325 330 335 Leu Ser Arg Ala Gly Ala Ala His Glu Phe Leu Glu His Asn Thr Thr 340 345 350 Ala Val Gly Arg Val Val Leu Lys Pro Gly Trp 355 360 <210> SEQ ID NO 8 <211> LENGTH: 294 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 8 Met Gly Ala Ala Ala Gly Glu Arg Arg Thr Leu Ser Arg Lys Arg Gly 5 10 15 Thr Thr Val Asp Val Pro Val Lys Gln Glu Ser Arg Gln Asp Arg Phe 20 25 30 Glu Asp Gln Asp Glu Asp Arg Phe Ala Ala Gln Glu Ser Ile Glu Cys 35 40 45 Ser Arg Leu Gly Asp Gly Ile Ala Leu Ala Glu Phe Ser Gly Ala His 50 55 60 Glu Gln Asn Pro Phe Ser Arg Ala Arg Met Arg Glu Leu Thr Ala Leu 65 70 75 80 Met Arg Glu Leu Asp Ala Asp Glu Lys Val Arg Cys Val Val Leu Tyr 85 90 95 Gly Gly Ala Gly Arg Ser Phe Gly Val Gly Gly Asp Phe His Glu Val 100 105 110 Ser Glu Phe Thr Gly Gly Asp Glu Val Asn Ala Trp Ile Asp Asp Ile 115 120 125 Thr Asp Leu Tyr Thr Thr Val Ala Ala Ile Ser Lys Pro Val Ile Ala 130 135 140 Ala Ile Asp Gly Tyr Ala Ile Gly Val Gly Leu Gln Ile Ser Leu Cys 145 150 155 160 Cys Asp Tyr Arg Leu Gly Ser Glu Gln Ala Arg Leu Val Met Pro Glu 165 170 175 Phe Arg Val Gly Ile Ala Cys Asn Phe Gly Gly Phe Met Leu Glu Ala 180 185 190 Ala Ala Gly Arg Thr Val Met Gln Arg Met Leu Leu Thr Cys Asp Glu 195 200 205 Trp Pro Ala Glu Arg Ala Leu Ala Asp Gly Leu Leu His Glu Thr Val 210 215 220 Ala Ser Pro Arg Leu Leu Asp Arg Ala Leu Glu Leu Ala Arg Thr Ile 225 230 235 240 Ser Gly Tyr Thr Ala Glu Ala Val Gln Ser Thr Arg Pro Arg Val Asn 245 250 255 Ala Pro Phe Val Ala Gly Leu Glu Arg Ile Arg Arg Glu Ala Lys Glu 260 265 270 Ser His Arg Arg Ala Phe Ala Ala Gly Glu Ala Gln Val Arg Met Arg 275 280 285 Arg Val Ile Gly Arg Ser 290 <210> SEQ ID NO 9 <211> LENGTH: 327 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 9 Val Ser Pro Arg Arg Leu Val Pro Ile Arg Pro Ala Asp His Leu Pro 5 10 15 Ala Leu Val Arg Leu Ala Ala Asp Arg Asp Arg Ala Ala Leu Gly Arg 20 25 30 Val Glu Val Gly Ala Thr Trp Ile Ala Gly Arg Leu Ala Ala Pro Gly 35 40 45 Leu Asp Pro Glu His Asp Thr Ala Leu Leu Thr Gly Ser Asp Gly Gln 50 55 60 Val Ala Gly Ala Val Trp Leu Ser Arg Ser Ser Gly Arg Ser Ala Trp 65 70 75 80 Asp Ala Glu Leu Leu Leu Ala Pro His Ala Thr Pro Asp Asp Ala Ala 85 90 95 Ser Leu Leu Asp Phe Ala His Arg Arg Cys Arg Thr Ile Ala Ala Gly 100 105 110 Arg Pro Glu Gly Glu Val Cys Leu Ser Cys Phe Val Ser Glu Arg Glu 115 120 125 Thr Ala Leu Arg Ile Ala Leu Ser Ala Tyr Gly Phe Ala Ala Pro Arg 130 135 140 Pro Tyr Leu Arg Met Ser Val Pro Leu Gly Gly Ala Thr Ala Gly Glu 145 150 155 160 Pro Pro Val Pro Gly Ala Val Val Arg Val Pro Glu Gly Glu Ala Gly 165 170 175 Leu Arg Ala Phe His Ala Val Lys Asn Arg Ala Phe Ser Ala Glu Glu 180 185 190 Ala Gly Met Glu Pro Asp Gly Phe Glu Glu Trp Leu Arg Trp Thr Gly 195 200 205 Ala Asp Pro Gly Ala Asp Pro Ser Gln Arg Ala Leu Leu Glu Leu Asp 210 215 220 Gly Glu Pro Val Gly Phe Ala Asn Val Thr Asp Arg Met Ala Gln Thr 225 230 235 240 Arg Gly Ala Ala Tyr Leu Arg Gln Ile Gly Val Leu Pro Arg Met Arg 245 250 255 Gly Arg Arg Leu Gly Ala Phe Leu Leu Arg Ser Val Met Ala Ala Ala 260 265 270 Arg Ala Arg Gly Arg Gly Glu Met Val Leu Thr Val Asp Thr Gly Asn 275 280 285 Arg Ala Gly Leu Ala Leu Tyr Arg Ala Thr Gly Trp Arg Glu Glu Ser 290 295 300 Arg Phe Tyr Asp Tyr Ala Tyr Arg Val Thr Ala Thr Pro Ala Pro Ala 305 310 315 320 Gly Glu Val Ser Ser Ala Arg 325 <210> SEQ ID NO 10 <211> LENGTH: 263 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 10 Met Pro Val Thr Gln Ser Ile Gln Ala Leu Ser Asp Glu Leu Arg Arg 5 10 15 Asp Gly Val Val Ala Leu Asp Asp Leu Val Pro Glu Ser Val Leu Glu 20 25 30 Val Met Arg Arg Gly Cys Ala Glu Leu Ile Gly Arg Thr Glu Arg Met 35 40 45 Arg Ile Ser Thr Glu Glu Trp Gln Leu Glu Ala Glu Gly Glu Gly Gly 50 55 60 Gly Trp Ala Ala Arg Ala Ala Gly Lys Glu Cys Ile Pro Gly Lys Val 65 70 75 80 Arg Ile Ile Gly Arg Ala His Glu His Ser Ala Asp Leu Ala Ala Val 85 90 95 Pro Asp Leu Val Gly Leu Asn Glu Lys Leu Ile Glu Pro Leu His Gly 100 105 110 Leu Pro Gly Asp Phe Tyr Asp Cys Phe Leu Trp Ala Lys Pro Ser Arg 115 120 125 Val Gly Ser Gln Lys Pro Trp His Gln Asp Ala Ile Phe Leu Ala Asp 130 135 140 Glu Trp His Glu Lys Tyr Val Asp Val Tyr Thr Ile Trp Ile Ala Val 145 150 155 160 Asp Asp Ala Arg Glu Asp Asn Gly Cys Leu Arg Phe Leu Pro Gly Ser 165 170 175 His Arg Glu Arg Lys Leu Tyr Glu Pro Asp Gly Ile Asp Pro Gly Asp 180 185 190 Ile Phe Ala Ser Pro Arg Glu Pro Ser Leu Asp Ile Ala Arg Ile Trp 195 200 205 Pro Gly Leu Thr Pro Val Thr Leu Pro Arg Lys Ala Gly Ser Ala Leu 210 215 220 Leu Phe Asn Gly Tyr Val Ala His Thr Ser Ala Pro Asn Thr Thr Glu 225 230 235 240 Asp Asp Arg Arg Ala Val Ser Tyr Cys Tyr Ser Leu Pro Arg His Pro 245 250 255 Ala Gly Pro Glu Ser Gly Arg 260 <210> SEQ ID NO 11 <211> LENGTH: 224 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 11 Met Val Cys Ala Ala Ser Ser Pro Ala Gly Ala Leu Leu Val Asp Trp 5 10 15 Gly Gly Val Leu Thr Gln Pro Phe Tyr Ala Gly Ile Ala Glu Trp Ala 20 25 30 Ala Arg Asp Gly Val Asp Ala Asp Ala Phe His Ala Leu Leu Ala Arg 35 40 45 His Leu Gly Pro Gly Ala Pro Gly Gly Ala Ala Ala Ser Val Phe His 50 55 60 Arg Val Glu Arg Gly Glu Val Pro Val Ala Glu Leu Glu Val Thr Leu 65 70 75 80 Ala Glu Ser Leu Arg Arg Pro Asp Gly Thr Gly Pro Pro Ala Glu Gly 85 90 95 Leu Ile Gln Arg Met Phe Gln Pro Phe Thr Met Ala Gly Ala Met Val 100 105 110 Glu Leu Val Arg Arg Val Arg Ala Ser Gly Ala Ala Val Ala Leu Leu 115 120 125 Ser Asn Ser Trp Gly His Thr Tyr Asp Arg Thr Gly Trp Asp Gly Leu 130 135 140 Phe Asp Glu Val Val Ile Ser Cys Glu Val Gly Met Arg Lys Pro Glu 145 150 155 160 Pro Glu Ile Tyr Arg Tyr Thr Ala Arg Arg Leu Gly Val Ala Pro Arg 165 170 175 Arg Cys Val Phe Leu Asp Asp Leu Gly Arg Asn Val Arg Ala Ala Ala 180 185 190 Ala Val Gly Met Thr Ala Val Gln His Thr Ser Val Glu Glu Ser Ser 195 200 205 Arg Glu Leu Ala Arg Phe Phe Asp Val Ser Pro Leu Pro Ala Gly Arg 210 215 220 <210> SEQ ID NO 12 <211> LENGTH: 476 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 12 Met Phe Asp Leu Arg Arg Ser Asp Val Ala Leu Leu Gln Ala Val Ala 5 10 15 Asp His Gly Ser Leu His Ala Ala Gln Arg Gln Gly Trp Val Thr Gln 20 25 30 Ser Ser Ala Ser Arg Arg Leu Thr Arg Leu Glu Arg Arg Leu Arg Thr 35 40 45 Val Leu Val Ser Arg Gly Ser Thr Gly Ala Arg Leu Thr Asp Glu Gly 50 55 60 His Ala Leu Leu His Ala Gly Gln Arg Leu Leu Gly Ala Ile Asp Phe 65 70 75 80 Ala Met Ala Asn Ala Ala Asp Thr Asp Glu Pro Gly Pro Arg Leu Arg 85 90 95 Val Leu Gln Met Ala Val Ser Thr Glu Tyr Thr Cys Glu Ala Gly Glu 100 105 110 Glu Pro Ala Val Gly Phe Pro Asp Val Val Phe Asp Leu Val Pro Ala 115 120 125 Ala Arg Gln Asp Val Trp Ser Arg Phe Asp Arg Tyr Ala Val Asp Ala 130 135 140 Ala Cys Gly Trp Ala Arg Ser Thr Pro Ala Leu Arg Arg Tyr Gly Ala 145 150 155 160 Asp Val Arg Leu Val Val Glu Glu Pro Gln Trp Val Ala Val Pro Arg 165 170 175 Gly His Pro Leu Ala Gly Arg Gly Ala Leu Gly Leu Glu Asp Leu Ala 180 185 190 Glu Ala Glu Trp Val Ala Ile Val Gly Glu Ser Thr His Glu Asp Leu 195 200 205 Ala Arg Ala Phe Ala Arg His Gly Leu Thr Pro Arg Val Gly Cys Thr 210 215 220 Val His Ser Arg Ser Ala Ala Ala Asp Leu Val Ala Arg Gly Tyr Gly 225 230 235 240 Phe Ala Leu Val Ser Pro Leu Cys Ala Ala Pro Val Glu Asp Ala Gly 245 250 255 Tyr Ala Leu Arg Pro Leu Arg Gln Gln Val Val Arg Arg Leu Phe Leu 260 265 270 Ala Thr Asp Pro Leu Leu Leu Pro Glu Ala Leu Ala Arg Asp Leu Cys 275 280 285 Thr Gly Leu Gln Arg Arg Tyr Val Gln His Ala Ala Glu Arg Asn Pro 290 295 300 Gly Tyr Leu Arg Ser Thr Thr Phe Pro Leu Pro Ala Ala Asp Leu Ser 305 310 315 320 Ala Pro Pro Pro Gly Arg Ser Ala Ala Thr Glu Pro Asp Gly Pro Arg 325 330 335 Asp Pro Leu Pro Phe Leu Val Cys Glu Arg His Trp Thr Ala Glu Gly 340 345 350 Pro Ser Ser Leu Val Glu Ala Glu His Leu Tyr Leu Leu Arg Val Ile 355 360 365 Glu Arg Thr Gly Ser Leu Asn Arg Ala Ala Ser Asp Leu Leu Ile Thr 370 375 380 Gln Pro Ala Leu Thr Arg Arg Ile His Arg Leu Glu Gln Val Cys Gly 385 390 395 400 Arg Thr Leu Val His Ser Ala Pro Arg Gly Thr Cys Leu Ser Pro Met 405 410 415 Ala Arg Arg Leu Leu His Cys Thr Glu Ala Ala Glu Asp Arg Leu Asp 420 425 430 Thr Leu Val Ala Ala Leu Arg Arg Ala Ala Ala Ser Thr Thr Pro Pro 435 440 445 Leu Pro Arg Gln Arg Pro Ala Gly Ser Gly Glu Thr Ser Lys Asn Arg 450 455 460 Ala Ser Ser Leu Leu Leu Ser Ser Thr Glu Val Cys 465 470 475 <210> SEQ ID NO 13 <211> LENGTH: 483 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 13 Val Ser Ala Pro Ala His Gly Ser Pro Ala Arg Gly Ala Ser Thr Val 5 10 15 Ala Leu Ala Val Leu Ala Ser Ala Cys Gly Leu Phe Ala Leu Met Gln 20 25 30 Leu Ala Val Thr Met Leu Leu Thr Gln Leu Arg His Gly Phe Gly Val 35 40 45 Gly Ala Ala Asp Thr Gly Trp Val Val Ser Gly His Leu Leu Val Ala 50 55 60 Cys Val Ala Thr Pro Val Val Gly Arg Leu Gly Asp Leu Tyr Gly Arg 65 70 75 80 Arg Arg Val Leu Leu Ala Val Leu Ala Val Phe Ala Ala Gly Gly Ala 85 90 95 Val Ala Ala Ser Ala Asp Thr Phe Gly Leu Leu Leu Ala Ala Arg Leu 100 105 110 Val Met Gly Val Ala Gly Gly Leu Phe Pro Leu Ala Val Gly Leu Val 115 120 125 Arg Glu Gly Phe Pro Ala Gly Ala Leu Ala Gly Pro Phe Gly Val Leu 130 135 140 Ser Ala Ser Phe Gly Val Gly Gly Gly Ala Gly Ile Met Leu Ala Gly 145 150 155 160 Val Val Glu Gly Asp Pro Asp Gly Tyr Arg Trp Val Phe Ala Thr Gly 165 170 175 Ala Ala Leu Ala Ala Leu Leu Leu Leu Ile Gly Ala Ala Val Leu Pro 180 185 190 Glu Thr Pro Arg Arg Ala Gly Gln Arg Leu Asp Ala Pro Gly Leu Thr 195 200 205 Leu Leu Ala Val Ser Ser Ala Leu Val Leu Leu Ala Leu Gly Arg Tyr 210 215 220 Gly Arg Asp Gly Ile Gly Ser Val Thr Gly Ser Thr Leu Leu Ala Gly 225 230 235 240 Ala Val Val Ser Gly Ala Ala Leu Leu Ala Trp Glu Arg Arg Thr Thr 245 250 255 Thr Pro Met Met Asp Leu Arg Leu Met Ser Arg Arg Pro Ile Trp Thr 260 265 270 Leu Asn Ala Val Ser Leu Leu Thr Gly Leu Val Met Phe Val Thr Gly 275 280 285 Thr Phe Pro Pro Ala Ile Ala Glu Ala Pro Arg Ser Ala Gly Gly Leu 290 295 300 Gly Val Ala Gly Leu Gly Val Ile Val Val Met Met Pro Met Glu Ile 305 310 315 320 Gly Thr Leu Gly Gly Gly Leu Leu Ser Gly Arg Leu Gly Arg Val Leu 325 330 335 Pro Pro Arg Ala Val Met Val Thr Gly Thr Val Leu Phe Ala Ala Ser 340 345 350 Ala Val Val Phe Ala Phe Leu Pro Val Ser Met Ala Ser Leu Ala Leu 355 360 365 Gly Thr Leu Leu Asn Gly Ala Ala Thr Gly Val Leu Gly Gly Ala Met 370 375 380 Thr Glu Leu Ile Thr Leu Ala Ser Pro Gly Gly Thr Thr Gly Val Val 385 390 395 400 Val Gly Thr Asn Ser Leu Leu Arg Ser Leu Gly Gly Ser Phe Gly Val 405 410 415 Gln Ala Gly Ser Met Val Leu Ala Ala Gly Thr Thr Gly Asp His Pro 420 425 430 Ser Pro Ala Ala Tyr Thr Leu Val Phe Ala Gly Thr Ala Val Leu Gly 435 440 445 Ala Leu Gly Ile Cys Ala Gly Ser Ala Phe Pro Arg Ala Ala Arg Ser 450 455 460 Asn Gly His Thr Thr Gly Thr Asn Pro Pro Thr Ala Gly Thr Val Asp 465 470 475 480 Arg Leu Thr <210> SEQ ID NO 14 <211> LENGTH: 681 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 14 Met Thr Val Pro Ala Ala Arg Ser Gly Arg Lys Val Tyr Phe Ile Gly 5 10 15 Leu Asn Ala Val Pro Phe Leu Pro Leu Val Ala Gly Leu Leu Arg Thr 20 25 30 Tyr Ala Glu Gln Asp Pro Arg Val Ala Ala Gly Tyr Asp Phe Gln Glu 35 40 45 Pro Val Phe Leu Val Asp Gly Val Gln Glu Met Ala Ala Gly Ile Thr 50 55 60 Asp Pro Asp Val Leu Ala Leu Ser Cys Tyr Val Trp Asn Phe Arg Arg 65 70 75 80 Gln Met Lys Val Ala Arg Leu Val Lys Glu Arg His Pro Gly Met Leu 85 90 95 Val Val Ala Gly Gly Pro His Val Pro Asp Arg Pro Gly Asp Phe Phe 100 105 110 Ala Arg His Pro Tyr Val Asp Val Leu Val His Gly Glu Gly Glu Thr 115 120 125 Ala Phe Arg Glu Leu Leu Ile Glu Arg Leu Ala Asp His Pro Asp Tyr 130 135 140 Thr Arg Val Pro Gly Val Ser Val Arg His Gly Thr Glu Ala Val Pro 145 150 155 160 Gly Arg Pro Ala Glu Arg Leu Pro Arg Arg Ile Glu Thr Pro Ser Pro 165 170 175 Tyr Leu Leu Gly Val Met Asp Gly Ala Val Ala Thr Cys Arg Gln Arg 180 185 190 Asp Leu Arg Phe Tyr Ala Leu Trp Glu Thr Asn Arg Gly Cys Pro Tyr 195 200 205 Ser Cys Ala Phe Cys Asp Trp Gly Ser Ala Thr Met Ser Ala Leu Arg 210 215 220 Leu Phe Asp Ala Glu Arg Leu Gln Glu Glu Ile Glu Trp Phe Ala Glu 225 230 235 240 His Asp Val Glu Asp Leu Phe Val Cys Asp Ala Asn Phe Gly Ile Leu 245 250 255 Pro Arg Asp Leu Glu Ile Ala Arg Ala Leu Ala Asp Ala Arg Ala Ala 260 265 270 Thr Gly Ala Pro Lys Leu Ile Arg Val Asn Phe Ala Lys Asn Ser Asn 275 280 285 Asp Arg Val Phe Glu Ile Ser Lys Thr Trp His Asp Ala Asp Leu Leu 290 295 300 Met Gly Thr Thr Leu Ser Met Gln Ser Thr Asp Leu Asp Val Leu Glu 305 310 315 320 Ala Ile Asp Arg Lys Asn Ile Gly Leu Glu Asn Tyr Arg Lys Leu Gln 325 330 335 Gln Arg Tyr Ala Thr Glu Asn Ile His Thr Tyr Thr Glu Leu Ile Leu 340 345 350 Gly Leu Pro Leu Glu Ser Pro Arg Ser Phe Arg Asp Gly Ile Gly Ser 355 360 365 Leu Leu Glu Ala Gly Asn His Glu Asp Ile Arg Val Tyr Glu Phe Gly 370 375 380 Ile Leu Pro Asn Ala Pro Ile Asn Thr Pro Glu Lys Ile Ala Gly Tyr 385 390 395 400 Gly Leu Arg Thr Val Pro Lys Arg Leu Tyr Val Glu Glu Pro Gly Thr 405 410 415 Pro Asp Asp Glu Ala Glu Thr Val Asp Met Val Met Glu Thr Asn Ala 420 425 430 Met Ser Arg Asp Glu Trp Val Asp Cys Phe Gly Phe Val Gln Ala Val 435 440 445 Gln Phe Leu His Asn Gly Cys Tyr Thr Arg Tyr Leu Ser Met Tyr Leu 450 455 460 Arg Gln Arg His Asp Ile Gly Tyr Thr Ala Phe Tyr Glu Arg Leu Gln 465 470 475 480 Gln Tyr Phe Gly Ala Arg Pro Asp Thr Val Leu Gly Ser Ile Tyr Leu 485 490 495 Arg Met Arg Lys Leu Tyr His Asp Tyr Ile Asp Ile Pro Glu Leu Pro 500 505 510 Leu Ala Asn Leu Val Ala Ser Gln Pro Asp Met Ala Ala Asp Leu Ala 515 520 525 Arg Tyr Gly Lys Arg Arg Gly Trp Thr Ile Asp Asn Trp Gly Trp Leu 530 535 540 Arg Ile Ala Asn Asp Phe Glu Arg Thr Tyr Thr Glu Leu Arg Asp Phe 545 550 555 560 Val Ala Ala Leu Gly Val Asp Asp Thr Ser Asp Pro Asp Leu Ala Glu 565 570 575 Val Phe Arg Phe Gln Gln Asp Val Met Leu Arg Pro Asp Tyr Asp Pro 580 585 590 Ala Ala Gly Arg Thr Thr Glu Tyr Thr Ala Asp Trp Pro Gly Tyr Phe 595 600 605 Thr Thr Gly Glu Leu Arg Arg Arg Pro Val Arg Met Arg Leu Ala Asp 610 615 620 Gln Arg Phe Gly Ala Asn Gly Arg Tyr Thr Pro Val Pro Gly Asp Leu 625 630 635 640 Lys Ala Phe Ala Arg Ala Ala Ile Gly Pro Ser Tyr Pro Val Ser Arg 645 650 655 Ile Gly His Tyr Arg His Arg Phe Glu Ala Ala Glu Val Thr Ser Pro 660 665 670 Ala Glu Pro Val Leu Thr Glu Gln Arg 675 680 <210> SEQ ID NO 15 <211> LENGTH: 474 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 15 Met Arg Val Leu Leu Val Trp Pro Arg Asn Glu Arg Ala Leu Leu Ser 5 10 15 Asp Arg Leu Ser Cys Cys Glu Pro Leu Pro Leu Glu Tyr Leu Ala Gly 20 25 30 Ala Leu Arg Gly Ala His Asp Val Thr Ile His Asp Leu Arg Val Asp 35 40 45 Thr Ser Leu Glu Glu Tyr Ala Ala Thr His Glu Ala Pro Asp Leu Ile 50 55 60 Gly Val Ala Ile Pro Tyr Thr Thr Ser Val Arg Val Ser Arg Asp Val 65 70 75 80 Thr His Gln Ala Arg Arg Leu Trp Pro Gly Thr Pro Ile Val Leu Gly 85 90 95 Gly His His Pro Thr Val Ser Ala Glu Trp Leu Thr Gly Phe Ala Ala 100 105 110 Asp Trp Ile Val Ala Gly Glu Gly Gly Gly Pro Leu Ala His Leu Ala 115 120 125 Ala Glu Leu Glu Ala Gly Arg Thr Pro Ala Pro Val Arg Gly Leu Ala 130 135 140 Pro Tyr Asp Ala Arg Thr Gly Leu Glu Arg Asp Arg Arg Pro Lys Pro 145 150 155 160 Ser Ala Leu Asp Asp Leu Pro Met Pro Asp Arg Thr Arg Leu Ala His 165 170 175 His Arg Gly Arg Tyr Phe His Ser Ile Tyr Arg Pro Val Ala Leu Ile 180 185 190 Arg Phe Thr Ala Gly Cys Pro Tyr Thr Cys Lys Phe Cys Ser Leu Trp 195 200 205 Arg Met Thr Asp Arg Arg Tyr Leu Val Lys Asp Ile Asp Arg Val Leu 210 215 220 Ala Glu Ile Ala Asp Ile Asp Gly Asp Asn Leu Tyr Val Val Asp Asp 225 230 235 240 Glu Ala Phe Ile Gln Pro Val Arg Met Leu Glu Leu Ala Asp Ala Ile 245 250 255 Asp Lys Ala Gly Phe Arg Lys Lys Phe His Met Tyr Val Arg Thr Asp 260 265 270 Thr Ala Leu Arg Arg Pro Asp Val Ile Ala Arg Trp Ala Glu Ile Gly 275 280 285 Leu Asp Ser Val Leu Val Gly Ala Glu Ser Met Thr Asp Glu Glu Leu 290 295 300 Thr Gly Tyr Arg Lys Gly Thr Asp Pro Gly Gln Thr Arg Arg Ala Leu 305 310 315 320 Asp Leu Phe His Gly Asn Gly Val Lys Val Arg Ala Asn Phe Ile Val 325 330 335 Gln Pro Asp Trp Ser Glu Ala Asp Phe Ala Arg Leu Gly Arg Thr Val 340 345 350 Asp Glu Leu Gln Val Asp Met Pro Ser Phe Ser Val Leu Thr Pro Leu 355 360 365 Pro Gly Thr Asp Leu Tyr Asp Glu Ala Lys Leu Gly Leu Ile Ser Asp 370 375 380 Asn Pro Glu Leu Phe Asp Cys Tyr His Ser Leu Phe Arg Thr Arg Leu 385 390 395 400 Pro Leu Glu Arg Phe Tyr Gly Glu Leu Ala Asp Leu Leu Ala Gly Ala 405 410 415 Ser Ala Arg Thr Ala Pro Gly Val Thr Gly Glu Ser Asp Pro Ser Val 420 425 430 Phe Tyr Tyr Ser Asp Asp Asp Ala Phe Asp Gln Met Leu Arg Glu Leu 435 440 445 Arg Arg Gly Ala Asp Trp Ser His Pro Arg Glu Ser Trp Ser Pro Thr 450 455 460 Arg Glu Pro Glu Thr Val Ala Gly Thr Gly 465 470 <210> SEQ ID NO 16 <211> LENGTH: 458 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 16 Met Ala Gly Phe Leu Leu Arg Cys Arg Pro Glu Gly Ala Val Pro Gln 5 10 15 His Leu Gly Ala Gly Thr Gly Leu Ala Thr Glu Val Thr Arg Asp Gly 20 25 30 Ala Asp Val Leu Val Val His Gly Asp Pro Leu Thr Pro Gly Gly Gln 35 40 45 Ala Pro Ile His Ala Pro Leu Asp Glu Leu Ile Ala Trp Thr Val Arg 50 55 60 Ala Tyr Ser Arg Phe Cys Ala Val Leu Val Arg Asp Asp Arg Ala Val 65 70 75 80 Leu Trp Ser Asp Asn Gly Ala Thr Cys Pro Leu His Tyr Ala Arg Gly 85 90 95 Ala Asp Asp Thr Leu Leu Val Ala Thr Ser Ala Gly Ala Leu Leu Pro 100 105 110 Leu Leu Gly Thr Ala Pro Val Leu Gly Glu Gly Asp Arg Ala Val Leu 115 120 125 Pro Gly Gly Arg Phe Ala Gly Val Thr Ala Val Pro Ala Gly Thr Ala 130 135 140 Val Thr Leu Ala Val Ala Gly Phe Asp Thr Glu Pro Leu Leu Thr Arg 145 150 155 160 Arg Tyr His Arg Leu Pro Ala Arg Pro Thr Glu Thr Asp Pro Glu Arg 165 170 175 Ala Val Thr Ala Val Arg Asp Ala Leu Thr His Ala Val Gly Arg Leu 180 185 190 Ala Thr Gly Leu Thr Glu Ala Gly Val Met Leu Ser Gly Gly Val Asp 195 200 205 Ser Ser Ser Val Ala Ala Leu Ala Ala Arg Glu Val Thr Ser Leu Ser 210 215 220 Thr Tyr Thr Val Gly Thr Pro Phe Gly Asp Glu Phe Ala Gln Ala Ala 225 230 235 240 Trp Phe Ala Glu Arg Leu Gly Ser Lys His His Glu Leu Val Phe Glu 245 250 255 Pro Glu Gln Leu Thr Ala Leu Leu Pro Glu Met Ile Arg Ser Leu Glu 260 265 270 Thr Trp Asp Leu Leu Thr Leu Gln Ile Ala Ala Pro Ala Cys Phe Leu 275 280 285 Leu Gly His Ile Ala Thr Gly Ala Arg Gln Val Met Leu Ser Gly Tyr 290 295 300 Gly Ala Asp Leu Ile Phe Ala Gly Leu Gly Gly Thr Gly Thr Glu Thr 305 310 315 320 Arg Ile Glu Arg Ser Val Ala Ala Gln Thr Ala Ala Thr Ala Val Ser 325 330 335 Asn Glu Phe Asn Pro Ala Tyr Ala Asp Ala Arg Asp Val Val Val Arg 340 345 350 Tyr Pro Tyr Trp Thr Arg Glu Val Met Ser Thr Ala Leu Gly Ile Arg 355 360 365 Gly Arg Leu Lys Val Arg Pro Asp Thr Ala Lys Trp Val Leu Arg Ser 370 375 380 Ala Val Thr Gly Ile Leu Pro Asp Glu Val Ala Trp Arg Pro Lys Arg 385 390 395 400 Gly Ile His Glu Gly Thr Ala Met Ser Arg Met Phe Ala Ala Ala Leu 405 410 415 Gly Ser Asp Asp Arg His Thr Gln Ala Arg Arg Leu Tyr Glu Met Ala 420 425 430 Thr Glu Val Phe Arg Asp Thr Ala Ala Gly Thr Asp Glu Leu Glu Gly 435 440 445 Ser Asp Glu Gly Leu Ala Gly Val Ala Ser 450 455 <210> SEQ ID NO 17 <211> LENGTH: 367 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 17 Met Pro Ser Pro Ser Lys Leu Arg Pro Ile Thr Asp Glu Asp Val Arg 5 10 15 Arg Ala Val Arg Leu His Phe Asp Pro Gln Asp Gly Thr Pro Tyr Trp 20 25 30 Leu Glu Arg Asp Arg Arg Asp Gly Thr Asp Ala Leu Arg Lys Val His 35 40 45 Gly Met Leu Asp Ala Gln Gln Leu Ile Gly Leu Arg Asp Gly Pro Asp 50 55 60 Gln Ala His Phe Glu Glu Ala Ser Arg Arg Thr Pro Leu Ala Asn Phe 65 70 75 80 Val Pro Arg Arg Val Leu Thr Glu Gly Gly Pro Leu Trp Ala Ala Gln 85 90 95 Thr Gly Gly Thr Thr Gly Pro Ala Lys His Gly Thr Trp Gly Ala Arg 100 105 110 Tyr Trp Ala Asp Ile Leu Glu Phe Ser Asp Glu Phe Leu Asp Leu His 115 120 125 Gly Val Pro Arg Gly Val Asp Trp Leu Phe Val Gly Pro Met Gly Pro 130 135 140 His Thr Thr Gly Arg Leu Val Val Ala Phe Ala Glu Arg Arg Gly Gly 145 150 155 160 Met Cys Phe Ser Val Asp Leu Asp Pro Arg Ile Val Lys Ile Phe Gly 165 170 175 Glu Glu Gly Met Thr Ala Ala Tyr Asp Arg Tyr Val Gln His Ile Trp 180 185 190 Asp Gln Val Ala Glu Val Ala Arg Ala Gln Arg Ile Gly Val Leu Phe 195 200 205 Cys Thr Ser Arg Leu Leu Glu Met Leu Pro Glu Arg Leu Gly Thr Glu 210 215 220 Ala Leu Pro Gly Leu Arg Ala Ile Val His Ala Gly Thr Thr Met Glu 225 230 235 240 Pro Glu Ser His Arg Gln Leu Arg Glu Asp Phe Phe Pro Gly Val Pro 245 250 255 Val Val Gly Met Tyr Gly Thr Ser Thr Thr Gly Ile Ser Trp Gln Lys 260 265 270 Pro Phe Glu Pro Glu Asp Asp His His Val Val Tyr Val Pro Cys Gln 275 280 285 Pro His Ile Ala Leu Asp Ala Val Asp Asp Asp Gly Asn Glu Val Pro 290 295 300 Phe Gly Glu Glu Gly Arg Val Arg Val Trp Arg Leu Thr Asp Asp Ala 305 310 315 320 Leu Leu Pro Gly Phe Leu Glu Arg Asp Arg Ala Arg Arg Val Gln Pro 325 330 335 Tyr Gly Ala Ala Ala Glu Arg Tyr Pro Trp Pro Trp Leu Gly Asp Pro 340 345 350 Tyr Ser Pro Glu Phe Thr Glu Gly Arg Arg Ile Glu Gly Val Tyr 355 360 365 <210> SEQ ID NO 18 <211> LENGTH: 472 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 18 Val Thr Thr Val Thr Thr Gly His Ala Gly Pro Gln Arg Ala Gly Ala 5 10 15 Val Leu Asp Val Pro Ala Tyr Ala Gly Arg Arg Pro Val Met Ser Ser 20 25 30 Arg Pro Ala Ala Leu Thr Gly Thr Thr Gly Glu Thr Val Ala Arg Val 35 40 45 Gly Ala Ala Gly Arg Leu Val Gln Phe Gln Met Ala Gln Glu Ala Ala 50 55 60 Ala Val Ala Arg Arg Leu Arg Ala Thr Asp Asp Asp Ala Trp Phe Ala 65 70 75 80 Leu Leu Arg Arg Ala Ala Asp Thr Leu Thr Ala Arg Val Ala Asp Gly 85 90 95 Thr Ala Gln Pro Trp Leu Thr Ala Leu Ser Ala Ala Ser Gly Leu Pro 100 105 110 Pro Arg Arg Ala Ala Arg Gly Ile Glu Thr Val Ala Ala Asp Leu Ala 115 120 125 Arg Met Asp Glu Ile Leu Ala Ala Gln Ser Pro Asp Gly Thr Val Ala 130 135 140 Ala Tyr Arg Thr Gly Gly His His Pro Arg Trp Ser Trp Arg Pro Ala 145 150 155 160 Gly Arg Ser Val Leu Val Lys Val Ala Asp Asn Phe Pro Thr Ile Asn 165 170 175 Ile Glu Trp Leu Gln Ala Leu Ala Ala Arg Arg Pro Val Leu Leu Ser 180 185 190 Thr Ser Arg His Asp Pro Phe Thr Pro Val Leu Leu Thr Glu Ala Leu 195 200 205 Tyr Glu Ala Gly Leu Pro Glu His Ala Val Ser Val Val His Gly Asp 210 215 220 Ala Pro Ala Leu Arg Arg Leu Ala Asp Gln Val Leu Trp Pro Gly Glu 225 230 235 240 Asp Val Pro Ala Asp Leu Pro Pro Gly Lys Ala Lys Thr Tyr His Phe 245 250 255 Gly Arg Ser Arg Ala Val Val Gly Ala Gly Ala Ala Asp Asp Ala Trp 260 265 270 Pro Arg Leu Ala Arg Ala Ala Phe Ala Gly Cys Gly Arg Leu Cys Thr 275 280 285 Asn Val Ser Ser Val Ile Ala Leu Gly Asp Ala Arg Gln Ala Ala Asp 290 295 300 Arg Leu Ala Glu Glu Phe Ala Thr Arg Pro Val Leu Pro Leu Asp Asp 305 310 315 320 Pro Ala Ala Thr Val Pro Ala Phe Pro Asp Arg Ala Arg Arg Asp Ala 325 330 335 Leu Ala Thr Arg Ile Glu Arg Glu Ile Ala Ala Gly Ala Val Asp Val 340 345 350 Thr Glu Ala Val Thr Gly Val Pro Leu Arg Val Glu Val Asp Gly Ala 355 360 365 Ala Phe Leu Arg Pro Thr Val Leu Leu Val Asp Pro Gly Ser Pro Leu 370 375 380 Phe Gly Thr Glu Leu Pro Phe Pro Phe Thr Ala Val Ala His Val Pro 385 390 395 400 Arg Ser Lys Ala Val Ala Ala Cys Ala Gly Ser Leu Ile Val Ser Val 405 410 415 Leu Gly Asp Ala Ala Gly Leu Leu Gly Ala Leu Ala Glu Glu Pro Gly 420 425 430 Val Asp Lys Val Phe Gly Ala Glu Glu Tyr Asp Arg Gly Tyr His Pro 435 440 445 Cys Asp Pro His Glu Gly Tyr Leu Ala Asp Phe Leu Phe Arg Lys Lys 450 455 460 Ala Val Ile Pro Gly Ala Ala Gly 465 470 <210> SEQ ID NO 19 <211> LENGTH: 484 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 19 Met Gln Val Leu Leu Val Asn Ala Arg Arg Ser Pro Tyr Ser Gly Glu 5 10 15 Ser Ile Ser Ala Pro Gln Leu Gly Leu Leu Ser Leu Ala Ser Val Leu 20 25 30 Arg Glu Gly Thr Phe His Asp Thr Ala Gly Thr Asp Val His Phe Ile 35 40 45 Asp Asp Gln Leu Phe Val Leu Gln Arg Pro Leu Ser Thr Pro Ser Glu 50 55 60 Phe Leu Arg Gly Tyr Arg Pro Asp Ile Val Gly Ile Gln Val Leu Thr 65 70 75 80 Ser Ser Leu Lys Asn Gly Ile Lys Leu Ala Ser Glu Val Arg His Arg 85 90 95 His Pro Asn Ala Leu Thr Val Leu Gly Gly Val Gly Ala Ser Pro Ile 100 105 110 Ala Arg Lys Leu Ile Glu Glu Asn Ala Ala Asp Val Val Val Arg Gly 115 120 125 Glu Gly Glu Tyr Ser Phe Ser Gln Leu Val His Glu Phe Gly Lys Asn 130 135 140 Gly Arg Lys Asn Phe Ala Lys Val Arg Gly Ile Thr Phe Arg Asp Asp 145 150 155 160 Glu Gly Glu Val Val Glu Thr Pro Ala Ala Pro Gln Val Val Asn Leu 165 170 175 Asp Lys Leu Pro Lys Pro Ala Arg Asp Leu Ala Asp Leu Asp Leu Tyr 180 185 190 Arg Arg Ile Ser Arg Gly Arg Ser Gly Asn Leu Val Thr Ser Arg Gly 195 200 205 Cys Ser Tyr Ala Cys Ala Tyr Cys Tyr Ser Lys His Gln Trp Gly Val 210 215 220 Gly Gln Arg Arg His Ser Ala Ala Arg Val Val Asp Glu Ile Arg Glu 225 230 235 240 Leu Val Glu Val Tyr Gly Phe Asp Arg Ile Arg Ile Glu Asp Asp Asp 245 250 255 Phe Val Glu Asp Val Pro Arg Met Gln Glu Leu Cys Asp Gly Ile Ala 260 265 270 Lys Ser Gly Leu Gln Gly Lys Phe Glu Trp Glu Ala Lys Ala Arg Pro 275 280 285 Asp Leu Ile Asn Asp Asp Met Ala Arg Met Leu Arg Glu Ser Gly Cys 290 295 300 Phe Arg Leu Leu Val Gly Val Glu Thr Leu Ser Trp Asn Leu Leu Lys 305 310 315 320 Arg Leu Gly Arg Pro Val Lys Val Asp Val Thr Glu Arg Ala Ile Ser 325 330 335 Cys Leu Thr Asn Asn Gly Ile Gly Val Gln Ala Thr Met Ile Leu Gly 340 345 350 Ile Pro Gly Glu Thr Asp Glu Ala Met Arg Thr Thr Ile Thr Trp Leu 355 360 365 Gln Ala Arg Leu Gly Lys Asn Lys His Asp Leu Val Ser Pro Cys Phe 370 375 380 Phe Val Pro Phe His Gln Glu Val Glu Lys Asp Met Ala Lys Arg Val 385 390 395 400 Asp Phe Thr Val Glu Thr Ser Asp Thr Asp Cys Tyr Thr Gly His Ile 405 410 415 Pro Val Thr Ser Ser Met Gly Ala Ser Ile Asp Glu Leu Trp Lys Leu 420 425 430 Tyr Asp Asp Met Thr Pro Ser Arg Ser Gln Gly Gln Tyr Lys Arg Ile 435 440 445 Ala Phe Leu Ala Asn Leu Gln Thr Val Gln Thr Arg Leu Gly Leu Leu 450 455 460 Asp Gly Asp Gly Ala Ser Asn Leu Ser Asn Glu Pro Ala Ala Leu Val 465 470 475 480 Pro Glu Val Gln <210> SEQ ID NO 20 <211> LENGTH: 259 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 20 Met Thr Ala Ser His Asp Thr Ala Asp Ala Thr Asp Arg Thr Val Gly 5 10 15 Ser Thr Ser Gly Glu Arg Ala Ala Phe Ala Arg Asp Gly Val Val Arg 20 25 30 Trp Gly Arg Leu Leu Thr Pro Asp Gln Ile Asp Ala Leu Arg Ser Ser 35 40 45 Val Glu Arg Ala Phe Phe Arg Asp Gly His Pro Ala Asp Gly Val Arg 50 55 60 Asp Leu Ser Glu Arg Gln Gly Arg Pro Leu Asp Leu Ala Leu Leu His 65 70 75 80 Lys Ile Asn Leu Trp Arg Thr Asp Glu Ala Cys Ala Ala Gln Val Ala 85 90 95 Arg Ala Asp Leu Ala Asp Arg Ala Glu Ala Leu Leu Gly Gly Pro Val 100 105 110 Arg Leu Tyr Arg Asp His Val Phe Tyr Lys Pro Pro Gly Lys Gly Asp 115 120 125 Arg Ser Arg Met Val Leu His Gln Asp Asn Arg Tyr Trp His Leu Asp 130 135 140 Pro Pro Glu Ala Ile Thr Val Trp Met Ala Leu Asp Asp Ala Thr Val 145 150 155 160 Glu Asn Gly Cys Val His Tyr Val Leu Gly Ser His Arg His Gly Arg 165 170 175 Val Glu His Val Arg Pro Glu Glu Gly Ala Val Met Ile Glu Ala Arg 180 185 190 Thr Glu Gln Glu Pro Val Ala Tyr Pro Ala Pro Ala Gly Asp Ala Leu 195 200 205 Val His Ser Val Asn Thr Leu His Gly Ser Gly Pro Asn Leu Ser Asp 210 215 220 Gly Pro Arg Arg Ala Tyr Val Val Val Tyr Val Arg Asp Gly Val Thr 225 230 235 240 Met Arg Gly Glu Pro Met Thr Ser Phe Pro Leu Val Gly Asp Leu Val 245 250 255 Arg Gly Gly <210> SEQ ID NO 21 <211> LENGTH: 240 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 21 Met Ala Asp Gly Pro Gly Ala Tyr Ala Asp Pro Val Asp Leu Asp Arg 5 10 15 Val Tyr Pro Arg His Arg Thr Asp Val Pro Thr Trp Leu Thr Gly Leu 20 25 30 Ala Arg Gln Ala Ala Asp Asp Ser Pro Pro Glu Leu Val Arg Tyr Leu 35 40 45 Leu Asp Asp Pro Ala Arg Gly Arg Pro Ser Ala Val Leu Val Leu Phe 50 55 60 Gly Thr Gly Asp Ala Gly Thr Asp Leu Leu Leu Val Arg Arg Ser Arg 65 70 75 80 Thr Leu Arg Ser His Pro Asp Glu Val Cys Phe Pro Gly Gly Ser Val 85 90 95 Ser Ala Gly Asp Arg Asp Val Val His Thr Ala Leu Arg Glu Ser Ala 100 105 110 Glu Glu Thr Gly Leu Asp Pro Ala Gly Val Ala Val Ala Gly Thr Leu 115 120 125 Arg Pro Leu Arg Ile Ala Trp Thr Asp Phe Arg Val Thr Pro Val Leu 130 135 140 Gly Trp Trp Gly Ala Glu Ala Glu Pro Arg Gly Asp Arg Gly Glu Val 145 150 155 160 Val Ser Val His Arg Val Pro Leu Ala Glu Phe Ala Asp Pro Ala Asn 165 170 175 Arg Phe Arg Val Arg Tyr Gln Asp Gly Tyr Ile Ser Pro Gly Phe Leu 180 185 190 Val Arg Glu Leu Phe Val Trp Gly Phe Thr Gly Ser Ile Val Asp Trp 195 200 205 Leu Met Arg Leu Ala Gly Trp Gly Arg Pro Trp Asp Thr Ser Arg Ile 210 215 220 Glu Glu Leu Pro Asp Ala Leu Arg Arg Tyr Gly Gly Gly Phe Gly Arg 225 230 235 240 <210> SEQ ID NO 22 <211> LENGTH: 329 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 22 Met Gly Ser His Arg Leu Leu Arg Ala Arg Ala Gly Thr Ala Gly Ala 5 10 15 Gly Pro Ser Arg Arg Gly Leu Ile Gly Thr Ser Leu Ala Gly Ile Ser 20 25 30 Gly Leu Ala Ala Gly Phe Gly Ser Leu Gly Ala Arg Pro Ala Ala Ala 35 40 45 Ala Arg Pro Gly Pro Val Gly Gly Thr Thr Arg Leu Arg Trp Phe Gly 50 55 60 Thr Asn Ala Trp Glu Ile Gly Phe Gly Gly Arg Thr Val Leu Val Asp 65 70 75 80 Pro Trp Leu Thr Arg Phe Thr Ala Gln Arg Pro Asp Gly Arg Val Asp 85 90 95 Pro Asp Thr Pro Leu Thr Val Asp His Ser Ala Val Asp Arg His Leu 100 105 110 Arg Ala Ala Asp Leu Ile Leu Leu Thr His Gly His Tyr Asp His Ile 115 120 125 Gly Asp Leu Pro Tyr Val Met Arg Lys Phe Pro Ser Ala Pro Val Val 130 135 140 Ala Thr Glu Thr His Ala His Leu Leu Thr Ala Met Gly Ala Pro Thr 145 150 155 160 Asp Arg Val Ile Trp Ala Arg Gly Gly Glu Tyr Leu Asp Phe Gly Asp 165 170 175 Phe Ala Val Arg Val Leu Pro Ser Leu His Ser Met Gly Pro Asp His 180 185 190 Arg Tyr Phe Ala Pro Gly Thr Leu Thr Ala Pro Pro Arg Arg Ala Arg 195 200 205 Thr Val Gly Asp Leu Leu Glu Gly Gly Thr Leu Ala Tyr His Ile Thr 210 215 220 Ser Asp Ser Gly Ala Ser Val Val Asn Ile Gly Thr Ala Asn Val Ile 225 230 235 240 Glu Arg Glu Leu Thr Gly Leu Arg Pro His Val Ala Ile Val Ala Val 245 250 255 Pro Pro Cys Gly Ala Thr His Arg Tyr Leu Glu Arg Val Leu Thr Ala 260 265 270 Leu Gly His Pro Pro His Val Ile Pro Thr His His Asp Gln Leu Asp 275 280 285 Thr Pro Leu Phe Arg Pro Ala Ser Val Asp Pro Gly Gln Met Arg Ser 290 295 300 Phe Arg Asp Gln Val Arg Ala Leu Gly Pro Gly Cys Ala Val Thr Glu 305 310 315 320 Pro Gln Tyr Cys Asp Ala Phe Thr Leu 325 <210> SEQ ID NO 23 <211> LENGTH: 399 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 23 Val Asp Pro Glu Ala Gly Ser Arg Ala Arg Gly Leu Lys Gly Val His 5 10 15 Arg Val Ser Ala Asn Ser Gly Gly Ile Gly Gly Val Pro Gly Pro His 20 25 30 Asn Gly Leu Thr Asp Val Pro Gly Val Arg Val Gly His Ala Gly Arg 35 40 45 Thr Gly Asp Gly Trp Leu Thr Gly Val Thr Val Val Leu Ala Pro Pro 50 55 60 Gly Gly Ala Val Ala Ala Val Asp Val Arg Gly Gly Gly Pro Gly Thr 65 70 75 80 Arg Glu Thr Asp Ala Leu Asp Pro Arg Asn Leu Val Gln Thr Ile Asp 85 90 95 Ala Val Val Leu Thr Gly Gly Ser Ala Phe Gly Leu Asp Ala Ala Gly 100 105 110 Gly Val Ala Ala Trp Leu Glu Glu Gln Gly Arg Gly Phe Pro Val Gly 115 120 125 Ala Asp Pro Ser Gln Val Val Pro Val Val Pro Ala Ala Ala Leu Phe 130 135 140 Asp Leu Gly Arg Gly Gly Thr Trp Arg Ala Arg Pro Asp Ala Ala Leu 145 150 155 160 Gly Arg Ala Ala Val Glu Ala Ala Ala Ala Arg Pro Glu Gly Asp Pro 165 170 175 Val Glu Gln Gly Gly Val Gly Ala Gly Thr Gly Ala Val Val Gly Gly 180 185 190 Leu Lys Gly Gly Ile Gly Thr Ala Ser Val Val Leu Asp Ser Gly Ala 195 200 205 Thr Val Ala Ala Leu Ala Ala Val Asn Ala Ala Gly Ser Ala Val Asp 210 215 220 Pro Ala Thr Gly Val Leu Tyr Gly Ala Arg Thr Gly Leu Pro Gly Glu 225 230 235 240 Phe Ala Gly Tyr Gly Val Pro Asp Ala Ile Gly Ala Asp Thr His Ala 245 250 255 Arg Ala Arg Ala Arg Leu Ala Glu Ala Ala Glu Glu Thr Ala Arg Arg 260 265 270 Arg Ala Gly Gly Ala Ala Thr Leu Asn Thr Thr Leu Ala Val Val Ala 275 280 285 Thr Asp Ala Thr Leu Thr Arg Ala Gln Ala Gln Lys Leu Ala Gly Thr 290 295 300 Ala His Asp Gly Leu Ala Arg Ala Val Arg Pro Val His Leu Leu Ser 305 310 315 320 Asp Gly Asp Thr Val Phe Ala Leu Ser Thr Gly Arg Arg Pro Leu Leu 325 330 335 Pro Asp Arg Pro Asp Ala Thr Ala Ala Arg Ala Phe Gly Val His Leu 340 345 350 Glu Ala Gly Ala Leu Asn Glu Val Leu Ala Ala Gly Ala Asp Val Leu 355 360 365 Thr Arg Ala Val Val His Ala Val Leu Ala Ala Thr Gly Val Asp Thr 370 375 380 Pro Gly Gly Val His Pro Ser Tyr Arg Glu Leu Tyr Ala Arg Pro 385 390 395 <210> SEQ ID NO 24 <211> LENGTH: 268 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 24 Met Asp Ala Asp Asp Cys Trp Ala Arg Ala Gly Thr Val Arg Ile Arg 5 10 15 Leu Leu Gly Pro Val Glu Leu Ala Cys Gly Thr Arg Pro Val Pro Val 20 25 30 Thr Gly Arg Arg Gln Leu Arg Val Val Ala Ala Leu Ala Leu Glu Ala 35 40 45 Gly Arg Val Leu Ser Thr Ala Gly Leu Ile Ala Ser Leu Trp Ala Asp 50 55 60 Glu Pro Pro Arg Thr Ala Ala Arg Gln Leu Gln Thr Ser Val Trp Met 65 70 75 80 Ile Arg Arg Ala Leu Ala Ser Val Gly Ala Pro Gln Cys Val Val Arg 85 90 95 Ser Thr Pro Ala Gly Tyr Leu Leu Asp Pro Ala His Tyr Glu Leu Asp 100 105 110 Ser Asp Arg Phe Arg His Ala Val Leu Thr Ala Arg Glu Leu Gln Arg 115 120 125 Asp Gly Arg Leu Ala Gln Ala Arg Ala Arg Val Asp Glu Gly Leu Ala 130 135 140 Leu Trp Arg Gly Pro Ala Leu Gly Ala Ala Ala Gly Ala Gly Leu Gln 145 150 155 160 Pro Arg Ala Arg Arg Leu Glu Glu Glu Arg Val Phe Ala Leu Glu Gln 165 170 175 Arg Ala Gly Leu Asp Leu Ala Leu Gly Arg His Glu Thr Ala Ile Gly 180 185 190 Glu Leu Leu Asp Leu Ile Ala Gln His Pro Leu Arg Glu Ala Ala Tyr 195 200 205 Ala Asp Leu Met Leu Ala Leu Tyr Arg Ser Gly Arg Gln Ser Asp Ala 210 215 220 Leu Ala Val Tyr Arg Arg Ala Gln Arg Val Leu Ala Asp Glu Leu Ala 225 230 235 240 Val Arg Pro Gly Pro Arg Leu Ala Gly Leu Glu Arg Ala Ile Leu Arg 245 250 255 Gln Asp Glu Ser Leu Leu Ala Gly Ala Ala Val Pro 260 265 <210> SEQ ID NO 25 <211> LENGTH: 137 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 25 Met Thr Pro His Asp Ser Ala Ser Pro Thr Ala Thr Val Arg Leu Asp 5 10 15 His Thr Ala Val Tyr Ala Ser Asp Arg Tyr Leu Ser Ala Glu Phe Ile 20 25 30 Ala Ala Ile Leu Gly Leu Glu Val Gly Lys Pro Phe Gly Pro Phe Leu 35 40 45 Pro Val Asp Leu Gly Asn Gly Val Thr Leu Asp Tyr Tyr Glu Lys Arg 50 55 60 Asp Glu Pro Ile Gln Ser Gln His Tyr Ala Phe Ile Val Pro Glu Asp 65 70 75 80 Arg Phe Asp Ala Val Ile Asp Arg Leu Glu Thr Val Gly Val Thr Tyr 85 90 95 Tyr Ala Asp Pro Ala His Thr Glu Pro Gly Arg Val Asn Gly Leu Phe 100 105 110 Gly Gly Arg Gly Ala Tyr Phe Ala Asp Pro Asp Gly His Asn Met Glu 115 120 125 Val Met Thr Arg Pro Tyr Val Arg Pro 130 135 <210> SEQ ID NO 26 <211> LENGTH: 180 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 26 Val Arg Arg Val Ser Pro Ala Trp Ser Gly Val Arg Gly Arg His Val 5 10 15 Arg Ser Ala Val Pro Ala Arg Arg Arg Ser Pro Val Thr Ser Ser Ala 20 25 30 Gly Leu Pro Val Leu Ser Ser Leu Asp Asp Leu Ala Arg Leu Ala Asp 35 40 45 Gly Ser Arg Gly Leu Tyr Val Arg Trp Ser Arg Gly Pro Arg Tyr Asp 50 55 60 Leu Arg Glu Thr Gly Ser Ala Asp Ser Leu Thr Gly Ile Ser Leu Pro 65 70 75 80 Gly Leu Ser Ala Asn Pro Leu Asp Val Asp Asp Trp Trp Ala Gly Arg 85 90 95 Pro Leu Arg Leu Trp Val Ala Arg Arg Leu Tyr Asp Tyr Cys His Leu 100 105 110 Arg His Asp Ile Gly Pro Gly Val Arg Pro Trp Val Leu Arg Gly Arg 115 120 125 Glu Val Gly Arg Gly Pro Asp Asn Glu Pro Leu Leu Thr Asp Val Arg 130 135 140 Pro Ile Ala Trp Ile Asp Pro Glu Val Ile His Glu Ala Arg Asp Glu 145 150 155 160 Val Ala Arg Gln Arg Gly Asp Trp Gly Pro Leu Arg Arg Pro Pro Gln 165 170 175 Ala Ser Gly Gly 180 <210> SEQ ID NO 27 <211> LENGTH: 62 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 27 Met Asn Thr Leu Ala Trp Trp Leu Arg Leu Thr Val Leu Ala Val Ala 5 10 15 Gly Gly Ala Val Ala Leu Leu Val Gln His Trp Thr Asp Gly Arg Pro 20 25 30 Trp Pro Glu Ala Gly Val Pro Ala Ala Leu Leu Val Val Val Ala Leu 35 40 45 Leu Met Gly Val Val Ser Arg Arg Ser Arg Arg Asp Leu Trp 50 55 60 <210> SEQ ID NO 28 <211> LENGTH: 253 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 28 Met Thr Asn Arg Thr Ala Val Leu Ser Asp Ile His Gly Val Leu Pro 5 10 15 Ala Leu Glu Ala Val Leu Ala Glu Pro Glu Val Arg Ala Ala Asp Arg 20 25 30 Val Val Leu Thr Gly Asp Ile Ala Cys Gly Pro Gln Pro Ala Glu Val 35 40 45 Leu Asp Leu Leu Thr Ala Leu Gly Asp Arg Val Thr Trp Val Ala Gly 50 55 60 Asn Ala Asp Arg Glu Leu Val Glu Phe Arg Arg Gly Val Arg Glu Thr 65 70 75 80 Ile Pro Asp Pro Ile Gly Pro Trp Ala Ala Arg Gln Leu Arg Pro Asp 85 90 95 His Leu Glu Leu Leu Ala Ser Leu Pro Leu Ser Val Arg Leu Pro Val 100 105 110 Ala Gly Leu Gly Thr Val Leu Phe Cys His Ala Thr Pro Arg Asp Asp 115 120 125 Glu Glu Val Val Val Val Asp Ser Arg Pro Asp Arg Trp Arg Glu Val 130 135 140 Phe Asp Gly Leu Gly Pro Asp Val Asp Ala Val Ile Cys Gly His Thr 145 150 155 160 His Met Pro Phe Val Arg Leu Ala His Gly Arg Leu Val Val Asn Pro 165 170 175 Gly Ser Val Gly Met Pro Tyr Gly Arg Ser Gly Ala His Trp Ala Leu 180 185 190 Leu Gly Pro Gly Val Asp Leu Arg Arg Thr Pro Tyr Asp Thr Asp Ala 195 200 205 Ala Ile Ala Arg Leu Thr Arg Asp Cys Gly Tyr Pro Ala Ile Ala Glu 210 215 220 Trp Ala Asp Tyr Tyr Val Arg Ala Arg Ala Thr Asp Thr Glu Ala Leu 225 230 235 240 Ala Ala Phe Gly Pro Arg Asp Gly Arg Gly Ala Glu Gly 245 250 <210> SEQ ID NO 29 <211> LENGTH: 61 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 29 Val Pro Cys Ala Pro Val Gly Pro Arg Thr Pro Ala Pro Pro Thr Ile 5 10 15 Trp Pro Ala Pro Arg Gly Pro Arg Ala Thr Arg Arg Gly Gly Thr Ala 20 25 30 Thr Ser Pro Arg Cys Ser Ser Thr Ile Cys Ser Ala Val Thr Trp Cys 35 40 45 Ala Ala Arg Tyr Gly Ser Val His Gln Phe Arg Leu Gly 50 55 60 <210> SEQ ID NO 30 <211> LENGTH: 143 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 30 Met Pro Glu Ser Ile Glu Asp Pro Phe Thr Pro Pro Ser Pro Glu Gln 5 10 15 Ala Arg Ala Glu Arg Val Ala Thr Ser Leu Phe Arg Ile Ala Glu Arg 20 25 30 His Ala Ala Thr Glu Glu Arg Arg Arg Arg Gln Thr His Pro Tyr Val 35 40 45 Leu Ala Pro His Glu Ala Val Arg Leu Val Ala Phe Leu Leu Ser Gly 50 55 60 Ala Ala Gln His Glu Glu Asp Glu Pro Glu Val Asp Arg Ala Asp Leu 65 70 75 80 Leu Ala Ala Leu Thr Leu Leu Pro Ala Ala Arg Ala Asp Leu Asp Glu 85 90 95 Ile Glu Ala Gly Leu Leu Lys Met Ala Arg Gly Arg Gly Leu Thr Trp 100 105 110 Pro Glu Ile Ala Phe Gly Leu Gly Leu Gly Thr Pro Gln Ala Ala Arg 115 120 125 Gln Arg Tyr Glu Arg Leu Ser Gly Arg Ile Ser Ala Asp Pro Glu 130 135 140 <210> SEQ ID NO 31 <211> LENGTH: 545 <212> TYPE: PRT <213> ORGANISM: Streptomyces cattleya <400> SEQUENCE: 31 Met Phe His Arg Ile Ser Arg Pro Gly Arg Gly Leu Arg Asp Gly Ala 5 10 15 Gly Thr Val Thr Arg Gly Arg Arg His Arg Pro Val Arg Gly Pro Gly 20 25 30 Glu Arg Ser Arg Cys Ser Arg Pro Ala Ser Ala Leu Ala Val Ala Leu 35 40 45 Thr Leu Ala Leu Thr Ala Gly Val Val Ser Pro Ala Ile Ala Ala Thr 50 55 60 Thr Pro Arg Ala Ala Pro Ser Ala Ala Pro Pro Pro Pro Ala Pro Thr 65 70 75 80 Thr Ala Ala Gly Asp Val Leu Val Asn Gly Trp Gly Asp Gly Ala Gly 85 90 95 Tyr His Leu Asp Val Ala Thr Gly Ser Gly Gly Tyr Asp Trp Arg Glu 100 105 110 Leu Ala Val Leu Arg Pro Ala Gly Ile Asp Asp Ser Ser Trp Thr Gly 115 120 125 Tyr Gln Cys Val Ser Gly Asp Gly Arg Tyr Ala Ala Val Ala Ile Leu 130 135 140 Pro Ala Ser Ala Val Asn Leu Ala Val Ala Arg Asp His Gly Ala Phe 145 150 155 160 Ala Tyr Ser Val Asp Leu Arg Ser Gly Ala Val Lys Pro Val Ala Ala 165 170 175 Gly Val Ala Leu Lys Tyr His Thr Pro Gly Cys Gly Thr Gly Asp Thr 180 185 190 Ala Glu Phe Thr Ile Asp Pro Gly Asn Asp Gln Arg Ala Thr Gln Val 195 200 205 Leu Ser Ala Asp Leu Pro Ser Gly Arg Leu Thr His Val Thr Thr Val 210 215 220 Pro Gly Gln Val Thr Ser Val Val Pro Ala Gly Asp Gly Pro Val Gly 225 230 235 240 Val Leu Gly Gly Glu Leu Val Arg Ile Pro Glu Asp Gly Gly Arg Thr 245 250 255 Ala Arg Pro Val Ala Leu Ala Ser Val Gly Gly Leu Ala Tyr Asp Leu 260 265 270 Arg Pro Ala Ala Gly Gly Gly Val Asp Phe Ala Val Gln Arg Ala Ala 275 280 285 Gly Arg Ser Ser Leu Ile Val Arg Glu Arg Ser Gly His Leu Thr Thr 290 295 300 Leu Gly Glu Gly Thr His Thr Gly Leu Arg Leu Met Gln Gly Arg Ala 305 310 315 320 Gly His Ala Leu Ala Leu Glu Ala Thr Arg Leu Val Pro Gly Ser Gly 325 330 335 Val Arg Ala Val Ala Thr Arg Gly Leu Pro Gly Ala Ala Thr Gly Val 340 345 350 Ser Leu Asp Gly Gly Ala Val Leu Gly Leu Gly Ala Arg Thr Ala Ala 355 360 365 Ser Ala Pro Leu Val Leu Ala Thr Arg Thr Gly Lys Val Leu Lys Arg 370 375 380 Ser Ala Ala Pro Ser Ala Arg Arg Pro Asp Thr Val Leu Pro Val Pro 385 390 395 400 Pro Pro Gly Ala Phe Gly Gly Ala Ala Gly Gly Leu Thr Pro Ser Ser 405 410 415 Ala Gly Val Arg Gly Thr Val Ser Pro Leu Thr Ala Thr Pro Lys Cys 420 425 430 Ala Val Gly Arg Asn Glu Glu Asn Arg Gln Val Met Gln Pro Gly Thr 435 440 445 Ala Gln Val Ser Trp Ala Val Gln Met Ala Glu Gln Gly Leu Leu Thr 450 455 460 Gly Ser Ala Tyr Gln Arg Pro Ala Asn Phe Ala Asn Leu Gly Leu Val 465 470 475 480 Ala Tyr Ser Pro Asn Gly Asp Phe Gly Lys Val Ala Leu His His Pro 485 490 495 Ser Gly Asp Ser Trp Asp Ser Val Pro Arg Ser Val Tyr Gln Ala Ile 500 505 510 Val Ala Gln Glu Ser Asn Tyr Ser Gln Ala Ser Trp His Ser Leu Pro 515 520 525 Gly Ile Pro Gly Asn Pro Leu Ile Ala Asp Tyr Tyr Gly Ala Gly Gly 530 535 540 Ser 545 <210> SEQ ID NO 32 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: degenerated oligonucleotide primer <400> SEQUENCE: 32 atcgtctaga csgasacstc saacgagtts 30 <210> SEQ ID NO 33 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: degenerated oligonucleotide primer <400> SEQUENCE: 33 atcgaagctt sgasccctcg tggacgcc 28 

1. A procedure for the isolation and purification of a DNA fragment, which contains the gene cluster for the thienamycin biosynthetic pathway of the bacterium Streptomyces cattleya, being included in a 32329 bp fragment of the S. cattleya genome. The process comprises the following steps: (a) forming a genomic DNA library of a thienamycin producing microorganism; (b) transfecting clones from said library into host cells; (c) designing degenerated oligonucleotides for the isolation of the thienamycin biosynthesis gene cluster. (d) constructing a probe comprising a nucleotide sequence from a thienamycin biosynthesis gene cluster. (e) hybridising said probe with a genomic DNA library derived from said microbe. (f) isolating said gene cluster from the positive hybridising clones.
 2. The invention provides a nucleic acid molecule according to claim 1, comprising: (a) a nucleotide sequence as shown in SEQ ID NO: 1; or (b) a nucleotide sequence which is the complement of SEQ ID NO: 1; or (c) a nucleotide sequence which is degenerate with SEQ ID NO: 1; or (d) a nucleotide sequence hybridising under conditions of high stringency to SEQ ID No. 1, to the complement of SEQ ID NO: 1, or to a hybridisation probe derived from SEQ ID NO: 1 or to the complement thereof; or (e) a nucleotide sequence having at least 80% sequence identity with SED ID NO: 1; (f) a nucleotide sequence having at least 65% sequence identity with SEQ ID NO: 1 wherein said sequence preferably encodes or is complementary to a sequence encoding at least a thienamycin biosynthetic enzyme or a part thereof.
 3. A nucleic acid molecule comprising a part of a nucleotide sequence as defined in claim 1 and claim 2, wherein said part is at least 15 nucleotides in length.
 4. A nucleic acid molecule as claimed in any one of claims 2 to 3 which encodes one or more polypetides or comprises one or more genetic elements, having functional activity in the synthesis of a β-lactam antibiotic or a β-lactam precursor.
 5. A nucleic acid molecule as claimed in claim 4, wherein said β-lactam antibiotic is thienamycin or a thienamycin precursor.
 6. A nucleic acid molecule as claimed in any one of claims 2 to 3 which encodes one or more polypeptides, or comprises one or more genes and/or one or more regulatory sequences, and/or one or more coding or noncoding genetic elements, having functional activity in the synthesis of a β-lactam antibiotic or a β-lactam precursor.
 7. A nucleic acid molecule as claimed in claim 6, wherein said β-lactam antibiotic or a β-lactam precursor is thienamycin or a thienamycin precursor.
 8. A nucleic acid molecule comprising a nucleotide sequence encoding one or more amino acid sequences selected from SEQ ID Nos: 2 to 31, or a nucleotide sequence which is complementary thereto or degenerate therewith or comprising a nucleotide sequence which encodes one or more amino acid sequences which exhibit at least 60% sequence identity with any one of SEQ ID Nos: 2 to
 31. 9. A nucleic acid molecule as claimed in claim 8 which encodes one or more amino acid sequences which exhibit at least 85% sequence identity with any one of SEQ ID Nos: 2 to
 31. 10. A polypeptide encoded by a nucleic acid molecule as defined in any one of claims 2 to
 9. 11. A polypeptide as claimed in claim 10, comprising: (a) all or part of an amino acid sequence as shown in any one or more of SEQ ID Nos: 2 to 31; or (b) all or part of an amino acid sequence which has at least 60% sequence identity with any one or more of SEQ ID Nos: 2 to
 31. 12. A polypeptide as claimed in claim 11, wherein said amino acid sequence at (b) has at least 85% sequence identity with any one or more of SEQ ID Nos: 2 to
 31. 13. A polypeptide as claimed in any one of claims 10 to 12 having functional activity in the synthesis of a carbapenem antibiotic or β-lactam moiety.
 14. A recombinant DNA molecule, which comprises the DNA fragment of any one of the claims 2 to 9, or a part thereof having similar characteristics, cloned in a vector replicating in Streptomyces or in E. coli.
 15. The recombinant DNA according to claim 14 which is the cosmid cosCAT25 deposited in E. coli strain ED8767/CAT25 with the accession number CECT
 5877. 16. The recombinant DNA according to claim 14 which is the plasmid pLE14 deposited in E. coli strain DH10B/LE14 with the accession number CECT
 5876. 17. The recombinant DNA according to claim 14 which is the plasmid pLE22 deposited in E. coli strain DH10B/LE22 with the accession number CECT
 5875. 18. A host cell or transgenic organism comprising a nucleic acid molecule as defined in any one of claims 2 to
 9. 19. A host cell or transgenic organism comprising a vector as defined in claim
 14. 20. Use of the genes derived from the DNA fragment of claims 2 to 9 in the production of β-lactam metabolites.
 21. Use of the genes derived from the DNA fragment of claims 2 to 9 in the production of thienamycin, thienamycin derivatives or thienamycin precursors.
 22. Use of the genes derived from the DNA fragment of claims 2 to 9 to increase β-lactam metabolites production.
 23. Use of the genes derived from the DNA fragment of claims 2 to 9 to increase production of thienamycin, thienamycin derivatives or thienamycin precursors.
 24. Use of a DNA molecule, as claimed in any one of the claims 2 to 9, in the inactivation of genes involved in thienamycin biosynthesis.
 25. Use of a DNA molecule, as claimed in any one of the claims 2 to 9, in PCR amplification techniques leading to the isolation and/or use of genes involved in thienamycin biosynthesis.
 26. Use of host cells or transgenic organisms as claimed in any one of claims 18 to 19 in the production of β-lactam metabolites.
 27. Use of host cells or transgenic organisms as claimed in any one of claims 18 to 19 in the production of thienamycin, thienamycin derivatives or thienamycin precursors.
 28. A process for increasing β-lactam production in a bacterial host, comprising transferring the DNA fragment of claim 2 to 9 into a Streptomyces host, cultivating the recombinant strain obtained, and isolating the β-lactam produced.
 29. The process according to claim 28, wherein the Streptomyces host is a Streptomyces cattleya host.
 30. The process according to claim 29, wherein the Streptomyces cattleya host is a mutant strain derived from S. cattleya NRRL
 8057. 31. A process according to claims 28 to 30, wherein the β-lactam compound is thienamycin, a thienamycin derivative or a thienamycin precursor.
 32. A process for generating thienamycin derivatives or thienamycin precursors by inactivation of genes derived from the DNA fragment of claims 2 to
 9. 33. A process as claimed in any one of the claims 20 to 27 for using the thienamycin intermediates or thienamycin derivatives as starting compounds for chemical synthesis of β-lactam products. 